Archive for the ‘ Nutrition ’ Category
Older adults who favored this eating style lost less brain volume, study finds
The ads started popping up about a decade ago on social media. Instead of selling alcohol with sex and romance, these ads had an edgier theme: Harried mothers chugging wine to cope with everyday stress. Women embracing quart-sized bottles of whiskey, and bellying up to bars to knock back vodka shots with men.
In this new strain of advertising, women’s liberation equaled heavy drinking, and alcohol researchers say it both heralded and promoted a profound cultural shift: Women in America are drinking far more, and far more frequently, than their mothers or grandmothers did, and alcohol consumption is ending their marriages, alienating them from their children and killing them in record numbers.
White women are particularly likely to drink dangerously, with more than a quarter (25%) drinking multiple times a week and the share of binge drinking up 40 percent since 1999, according to a Washington Post analysis of federal health data. In 2013, more than a million women of all races wound up in emergency rooms as a result of heavy drinking, with women in middle age most likely to suffer severe intoxication.
This behavior has contributed to a startling increase in early mortality. The rate of alcohol-related deaths for white women ages 35 to 54 has more than doubled since 1999, according to The Post analysis, accounting for 8 percent of deaths in this age group in 2015.
“It is a looming health crisis,” said Katherine M. Keyes, an alcohol researcher at Columbia University.
Although independent researchers are increasingly convinced that any amount of alcohol poses serious health risks, American women are still receiving mixed messages. Parts of the federal government continue to advance the idea that moderate drinking may be good for you. Meanwhile, many ads for alcohol — particularly on social media — appear to promote excessive drinking, which is universally recognized as potentially deadly. These ads also appear to violate the industry’s code of ethics, according to a Post analysis of alcohol marketing.
For example, when girl-power heroine Amy Schumer guzzled Bandit boxed wine in the movie “Trainwreck,” Bandit’s producer, Trinchero Family Estates, promoted the scene on social media. Young women responded with photos of themselves chugging Bandit. Within months, Trinchero said, sales of boxed wines — sometimes called “binge in a box” — jumped 22 percent.
“We saw it first with tobacco, marketing it to women as their right to smoke. Then we saw lung cancer deaths surpass deaths from breast cancer,” said Rear Adm. Susan Blumenthal, a former assistant surgeon general and an expert on women’s health issues. “Now it’s happening with alcohol, and it’s become an equal rights tragedy.”
Alcohol marketing is regulated primarily by industry trade groups, but dozens of studies have found lapses in their record of enforcing the rules. As a result, an international group of public health experts convened by the World Health Organization’s regional office in Washington, D.C., plans to call in January for governments worldwide to consider legislation similar to laws adopted a decade ago to sharply curtail tobacco advertising.
Officials with the Distilled Spirits Council of the United States, one of the largest U.S. trade groups, defend their record of oversight, saying it has received high marks from federal regulators.
DISCUS tells members that ads should not “in any way suggest that intoxication is socially acceptable conduct.” The Beer Institute tells members that their “marketing materials should not depict situations where beer is being consumed rapidly, excessively.” And the Wine Institute prohibits ads that make “any suggestion that excessive drinking or loss of control is amusing or a proper subject for amusement” or that directly associate use of wine with “social, physical or personal problem solving.”
But these rules appear regularly to be flouted, particularly on alcohol companies’ websites and social-media feeds, which are soaking up a growing share of the more than $2 billion the industry is expected to spend on advertising this year. And the trade groups acknowledge that they do not investigate or act on possible violations unless they receive a formal complaint.
Some of the edgiest ads appear on social media — Facebook, Twitter, Instagram — where they can be narrowly targeted toward the inboxes and desperate little lives of the most eager consumers.
Jokes about becoming inebriated are common.
Women also are frequently shown drinking to cope with daily stress. In one image that appeared on a company website, two white women wearing prim, narrow-brimmed hats, button earrings and wash-and-set hair confer side by side. “How much do you spend on a bottle of wine?” one asks. The other answers, “I would guess about half an hour …” At the bottom is the name of the wine:
Mommy’s Time Out.
Another ad on a company website features a white woman wearing pearls and an apron. “The most expensive part of having kids is all the wine you have to drink,” it says above the name of the wine:
This spring, Mad Housewife offered a Mother’s Day promotion: a six-pack of wine called
Mommy’s Little Helper.
“The rise in hazardous drinking among women is not all due to the ads. But the ads have played a role in creating a cultural climate that says it’s funny when women drink heavily,” said Jean Kilbourne, who has produced several films and books about alcohol marketing to women. “Most importantly, they’ve played a role in normalizing it.
World’s Oldest PersonBorn on 29 November 1899, Emma Morano is 116 years old and is currently the world’s oldest living person. She is believed to be the last person living born in the 19th century. So, what’s her secret to longevity? Well, she has been following the same diet for around 90 years. She has three eggs per day (two raw, one cooked), fresh Italian pasta and a dish of raw meat.
Dr. Mercola discusses the role of B vitamins and other valuable nutrients to support brain health.
Reprinted with the kind permission of Dr. Mercola.
By Dr. Mercola
A number of studies have investigated the impact of vitamin supplementation to prevent and/or treat cognitive dysfunction and decline.
It’s well-established that healthy fats such as animal-based omega-3 fats are really important for brain health, but other nutrients such as vitamins are also necessary for optimal brain function.
Most recently, a Korean study1 concluded that giving a multivitamin supplement to seniors suffering from mild cognitive impairment and depression helped improve both conditions.
B vitamins in particular, especially folate (B9, aka folic acid in its synthetic form) and vitamins B6 and B12, have made headlines for their powerful role in preventing cognitive decline and more serious dementia such as Alzheimer’s disease.
Mental fogginess and problems with memory are actually two of the top warning signs that you have vitamin B12 deficiency, indicating its importance for brain health.
B Vitamins and Omega-3 — An Important Combo for Brain Health
“There was a significant interaction between B vitamin treatment and plasma combined omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) on brain atrophy rates.
B Vitamins Significantly Slow Brain Shrinkage
” … B vitamins lower homocysteine, which directly leads to a decrease in GM [gray matter] atrophy, thereby slowing cognitive decline.
|Nutrient||Dietary Sources||Supplement Recommendations|
Fatty fish that is low in mercury, such as wild-caught Alaskan salmon, sardines, and anchovies, as well as organic grass-fed beef.10
Sardines, in particular, are one of the most concentrated sources of omega-3 fats, with one serving containing more than 50 percent of your recommended daily value.
|Antarctic krill oil is a sustainable choice. It also has the added benefit of containing natural astaxanthin, which helps prevent oxidation.
Another good option is wild-caught Alaskan salmon oil.
|Vitamin B6||Turkey, beef, chicken, wild-caught salmon, sweet potatoes, potatoes, sunflower seeds, pistachios, avocado, spinach and banana.11,12||
Nutritional yeast is an excellent source of B vitamins, especially B6.13One serving (2 tablespoons) contains nearly 10 mg of vitamin B6.
Not to be confused with Brewer’s yeast or other active yeasts, nutritional yeast is made from an organism grown on molasses, which is then harvested and dried to deactivate the yeast.
It has a pleasant cheesy flavor and can be added to a number of different dishes. For tips, see this vegan blog post.14
|Folate (B9)||Fresh, raw, and organic leafy green vegetables, especially broccoli, asparagus, spinach, and turnip greens, and a wide variety of beans, especially lentils, but also pinto beans, garbanzo beans, navy and black beans, and kidney beans.15||
Folic acid is a synthetic type of B vitamin used in supplements; folate is the natural form found in foods.
Think: folate comes from foliage(edible leafy plants).
For folic acid to be of use, it must first be activated into its biologically active form — L-5-MTHF.
This is the form able to cross the blood-brain barrier to give you the brain benefits noted.
Nearly half of the population has difficulty converting folic acid into the bioactive form due to a genetic reduction in enzyme activity.
For this reason, if you take a B vitamin supplement, make sure it contains natural folate rather than synthetic folic acid.
Nutritional yeast is an excellent source.16
Vitamin B12 is found almost exclusively in animal tissues, including foods like beef and beef liver, lamb, snapper, venison, salmon, shrimp, scallops, poultry, eggs, and dairy products.
The few plant foods that are sources of B12 are actually B12 analogs that block the uptake of true B12.
Also consider limiting sugar and eating fermented foods.
The entire B group vitamin series is produced within your gut, assuming you have healthy gut flora.
Eating real food, ideally organic, along with fermented foods will provide your microbiome with important fiber and beneficial bacteria to help optimize your internal vitamin B production.
|Nutritional yeast is also high in B12, and is highly recommended for vegetarians and vegans.
One serving (2 tbsp) provides nearly 8 micrograms (mcg) of natural vitamin B12.17
Sublingual (under-the-tongue) fine mist spray or vitamin B12 injections are also effective, as they allow the large B12 molecule to be absorbed directly into your bloodstream.
|Vitamin C||Sweet peppers, chili peppers, Brussel sprouts, broccoli, artichoke, sweet potato, tomato, cauliflower, kale, papaya, strawberries, oranges, kiwi, grapefruit, cantaloupe, and lemon.
To boost your intake of fruits and vegetables, consider juicing. As an alternative, you can also make fermented vegetables at home.
The vitamin C in sauerkraut (fermented cabbage) is about six times higher than in the same helping of unfermented cabbage, so it’s an excellent way to boost your vitamin C intake.
The most effective form of oral vitamin C is liposomal vitamin C.
It’s not associated with many of the complications of traditional vitamin C or ascorbic acid (such as gastrointestinal distress), which will allow you to achieve higher intracellular concentrations.
You can expect a significant rise in plasma vitamin C concentration at doses between 30 and 100 mg/day.
Taking vitamin C frequently throughout the day is more effective than taking one large dose once a day.
|Vitamin D||Vitamin D is created naturally when your skin is exposed to sunshine.
While you can get some vitamin D from grass-fed meats and other whole foods and fortified foods, sun exposure is an ideal primary source.
|When taking supplemental vitamin D, also be sure to increase your intake of vitamin K2 and magnesium, either from food or a supplement.|
Sources and References
When colonic bacteria move out of the colon and into the small intestine, a condition called small intestinal bacterial overgrowth, develops.30 Small intestinal bacterial overgrowth is associated with carbohydrate malabsorption and may also result in intestinal inflammation. This inflammatory response can then cause the normally tight intestinal barrier to leak, permitting bacteria and toxins to enter the bloodstream, where they may contribute to symptoms of food allergy and food sensitivity.10-12
1. Remove harmful toxins. Eliminating foods Becca was sensitive to was the first step; we identified them with a food allergy test. She ended up taking out gluten, dairy, eggs, bananas, potatoes, corn and a few other vegetables. I also had her remove red meat from her diet. I also wanted to eradicate the yeast and parasites in her body. This we did with a combination of anti-fungal and antibacterial botanicals. She concentrated on eating a diet heavy in fish, poultry, vegetables, rice, olive and coconut oil.2. Replace digestive functionality. Often, bloating and gas indicates poor digestive capability and, indeed, Becca’s CDSA test confirmed that. We had her take a digestive enzyme with every meal.3. Re-inoculate the gut with good bacteria. Probiotics (20-30 billion live organisms) at each meal were necessary to improve intestinal immune function.4. Repair the gut lining. It’s imperative to heal the gut lining with things like l-glutamine, fish oils and n-acetyl-d-glucosamine.5. A few other things we did: biotherapeutic drainage to detoxify her liver, adrenal support with adaptogenic herbs, lots of greens drinks to provide energy and aid in detox, and stress reduction techniques such as craniosacral therapy.
By Alicia Nadil
Do you remember how easy it was in youth to consume a high-calorie meal and suffer no unpleasant aftereffects?
One reason we internally managed foods so easily back in those days were the massive amounts of digestive juices we produced that efficiently broke down foods for healthy absorption.
Contrast this to what many adults take after meals, such as over-the-counter drugs like Alka-Seltzer® and Pepto-Bismol® to relieve gas, bloating, cramping, and other digestive problems. These drugs can provide temporary relief, but they don’t treat the underlying cause of the problem.
Over-the-counter drugs are a huge business.1,2 In the United States alone, people with digestive discomfort spend $9.5 billion on over-the-counter stomach remedies, and studies show that people taking such medications commonly report not thinking that their problem was serious enough to seek medical attention.2-4
A national survey in 2013 demonstrated that 72% of respondents experienced one or more symptoms such as diarrhea, gas, bloating, stomach pain, frequent bowel movements, unexplained weight loss, or nonspecific abdominal discomfort and 74% of those surveyed reported living with their symptoms for more than six months.4
Unfortunately, over-the-counter drugs could be masking a more serious issue.
After-meal abdominal symptoms often represent poor digestion of complex foods, causing one to be unable to fully absorb nutrients needed for optimal health. This can lead to chronic low-level malnutrition and/or stomach distress after most meals.5,6
A common cause of these widespread digestive problems is the age-related decline of active enzymes that help break down foods into absorbable nutrients.7-9
A second major cause of abdominal symptoms in older adults is the chronic imbalance of the trillions of beneficial organisms that populate our gastrointestinal (GI) tract. Such disturbances contribute to nutrient malabsorption, while also producing inflammation that can weaken the intestinal barrier and allow bacteria and toxins into the circulation where they may aggravate food allergies and sensitivities.10-13
Fortunately, studies show that it is possible to address both of these underlying causes of gastro-intestinal distresses. By properly supplementing with digestive enzymes and probiotics, healthy older adults can take meaningful steps to maintain good digestive health. The result can be better digestion, less abdominal stress, and greater retention of nutrients.
Why Digestive Enzymes Are so Important
In order for the food we eat to be absorbed into our bloodstream, the actions of powerful enzymes are required to break down the food in order to extract vital nutrients. Each of the three major food groups—carbohydrates, proteins, and fats—must be broken down by specific enzymes before being absorbed by cells in the digestive tract.
When the digestive tract is in good working order, food is almost completely broken down by the time it reaches the end of our small intestine, leaving few undigested food molecules to pass into the colon. The result is a well-nourished body that continuously renews itself, and a comfortable sensation following a meal.
With age, the production of normal digestive enzymes begins to fall off, leaving significant amounts of all three major food groups (fats, proteins, and carbohydrates) to pass undigested into the large intestine, or colon.8,9,14
This can lead to bloating, gas, diarrhea, and cramping—and even worse, can contribute to the malnutrition that threatens older people as a result of lost appetite and changes in muscle and fat stores.15,16 That’s why the proper complement of healthy enzymes is crucial not just for healthy digestion—but for good health in general.
What You Need to Know
Enzymes and Probiotics for Healthy Digestion
- Research indicates over 70% of Americans report feeling discomfort, bloating, gas, cramps, or urgency to defecate following a meal.
- This problem is especially prevalent in older adults, whose natural production of digestive enzymes dwindles with age.
- Loss of normal balance of beneficial gastrointestinal microbes further exacerbates symptoms.
- Supplementation with digestive enzymes that break down starches, protein, fats, and fiber is a proven method to reduce symptoms and improve nutritional status.
- Supplementation with B. coagulans, a beneficial probiotic microbe, can further improve comfort and reduce symptoms by balancing your population of intestinal organisms.
- If you suffer from any degree of discomfort following what should be a pleasant and fulfilling meal, it’s time to add digestive enzymes and sustainable probiotic bacteria to your regimen.
Improving Digestive Comfort and Function
A natural solution to declining levels of digestive enzymes is to supplement with digestive enzymes that cover the major needs of the body to break down all classes of food, including starch, proteins, fats, cellulose, and milk.
For optimal digestion, it is important to include these major digestive enzymes:
- Amylase to break down starch and short sugar chains called oligosaccharides,
- Protease to help break down proteins,
- Lipase to break down fats,
- Cellulase to break down the indigestible polysaccharide in dietary cellulose, and
- Lactase to break down lactose (milk sugar).
People suffering from pancreatic insufficiency as a result of cystic fibrosis, pancreatic surgery, or trauma have long used supplemental digestive enzymes.17 But researchers have recognized that the addition of digestive enzymes is beneficial to healthy individuals as well.
In various studies, each of these major enzymes has shown specific benefits in digesting food.
Animal studies have repeatedly demonstrated that when supplemental digestive enzymes are added to the normal food supply, they can significantly improve digestibility of dietary foods, improve nutrient absorption, reduce gas production, and, in at least one case, reduce food intake, as a result of improved nutritional status.5,18,19 Furthermore, in stressed or aged animals, a mix of pancreatic digestive enzymes improved muscle wasting in addition to the other benefits.5
Human studies are now revealing similarly impressive results for supplemental digestive enzymes. In a study of adults with chronic pancreatic insufficiency, in which the subjects were unable to fully digest and absorb fats and proteins, researchers tested two pancreatic enzyme replacement products. A supplement with bromelain proved significantly more effective at improving both protein and fat digestion and absorption.20
Pancreatic lipase (the fat-digesting enzyme) has been routinely used for years in people with pancreatic insufficiency to assist with digestion.21 A study in healthy volunteers demonstrated that the use of this enzyme could be beneficial in others as well.
For the study, subjects ate 185 grams (about 6 ounces) of cookies containing 1,196 calories and 72 grams (about 2.5 ounces) of fat, along with capsules of lipase or a placebo.22 They were then followed for up to 17 hours. Compared to placebo patients, patients supplemented with lipase showed significant reductions in bloating over the entire period, with significant reductions in bloating, gas, and fullness later in the day.
Lactase , the enzyme that breaks down lactose, or “milk sugar,” is sharply reduced in adults from everywhere except Northern Europe, and both human and animal studies demonstrate that this lactase deficiency increases with advancing age.8,23 Deficiency of lactase produces a condition known as lactose intolerance, characterized by cramps, bloating, gas, and often diarrhea following consumption of milk products. Lactose intolerance is known to be a significant problem in the elderly, and can lead to insufficient calcium intake, resulting in greater risks of osteoporosis and subsequent fractures.9,24,25 Thus, it is especially important in older adults to be capable of comfortably consuming milk products to help avoid osteoporosis.
Studies show that supplementation with lactase produces a significant reduction in excretion of hydrogen in the breath (a marker of improved lactose digestion), while also significantly reducing symptoms of abdominal cramping, belching, flatulence, bloating, and diarrhea.26
Consuming these specific digestive enzymes would provide comprehensive assistance to one’s ability to digest foods in a more youthful and tolerant fashion—and would also help relieve discomforts after eating, as well as improve your overall nutritional status.
The Five Most Prevalent Digestive Enzymes
Each major food group has a specific type of enzyme responsible for its breakdown. Deficiency in any of these enzymes can lead to a wide range of common intestinal troubles. There are five major digestive enzymes that need to be at healthy levels for the digestion of food without painful or embarrassing side effects. These include amylase, protease, lipase, cellulose, and lactase.
Carbohydrates and starches are digested by the enzyme amylase. A deficiency in amylases causes undigested carbohydrate molecules to pass on to the colon, where gut organisms break them down, literally fermenting them to produce carbon dioxide and water that lead to cramping, flatulence, and diarrhea.41,42,43
Proteins are digested by the protease enzymes. A deficiency in proteases leaves protein molecules or fragments undigested. Again, these pass on to the colon, in this case giving rise to a host of unpleasant-smelling and potentially toxic molecules.44-47 Undigested protein in the colon has also been associated with colon cancer initiation, though the exact mechanisms are still under investigation.48
Fats are digested by the lipase enzymes. A deficiency in lipases leaves long-chain fats undigested. Undigested fats cannot be absorbed anywhere in the body and are typically passed on through the GI tract to produce greasy, fatty stools, cramping, and even malnutrition when fat-soluble vitamins are lost.17
Though several different digestive system organs produce some digestive enzymes, the pancreas makes all three of these essential digestive enzymes.49 Loss of pancreatic function is therefore a common cause of after-meal indigestion and other symptoms. Pancreatic insufficiency was long thought to be found only in patients with disorders of the pancreas itself, such as cystic fibrosis, pancreatitis, or pancreatic tumors. However, it is now recognized as being associated with aging.9,17,50,51 One recent study found pancreatic insufficiency in more than 7% of a large group of patients with general abdominal pain and discomfort.32
Cellulase is the enzyme that breaks down cellulose, the indigestible polysaccharide in dietary fiber.52 Fiber is increasingly recognized as vital for healthy digestion because, though humans cannot break it down, it feeds the beneficial organisms in our colons, which use it to produce beneficial short-chain fatty acids that nourish our colonic cells and help to prevent cancer.53 But, precisely because we cannot digest fiber ourselves, it can produce symptoms of bloating, flatulence, diarrhea, and constipation when broken down by our intestinal tenants.54
Lastly, lactase is the enzyme that breaks down milk sugar (lactose).55 A deficiency in lactase can prevent the body from breaking down lactose, leading to lactose intolerance, which can lead to abdominal cramping, belching, flatulence, diarrhea, and bloating.56
In addition to having reduced levels of digestive enzymes, another cause of digestive malfunction and after-meal discomfort occurs when the normal microbial populations become imbalanced.27
The body relies heavily on the teeming communities of bacteria that live in the large intestine, or colon. Like any community, this group of microbes, collectively known as the intestinal microbiome, functions best when its occupants are richly diverse and respect one another’s boundaries. If those properties are not present, symptoms of indigestion may arise.28,29
When colonic bacteria move out of the colon and into the small intestine, a condition called small intestinal bacterial overgrowth, develops.30 Small intestinal bacterial overgrowth is associated with carbohydrate malabsorption and may also result in intestinal inflammation. This inflammatory response can then cause the normally tight intestinal barrier to leak, permitting bacteria and toxins to enter the bloodstream, where they may contribute to symptoms of food allergy and food sensitivity.10-12
A related condition is intestinal dysbiosis, in which the natural balance of beneficial bacteria living in the gut becomes disturbed.31 This is a huge and growing area of medical research, as researchers learn that it does not take a true pathogen (disease-causing organism) to produce abdominal symptoms and increase the risk for a host of life-shortening disorders.
In fact, simply having the wrong mix of bacteria in your intestines can set the stage for obesity, cardiovascular disease, and many other chronic, age-associated conditions.32,33 Studies show that as many as 73% of people with abdominal complaints have some form of dysbiosis.32
In addition to causing GI discomfort and related symptoms, all of these problems can contribute to malnutrition, a serious and growing problem in older adults—one that exacerbates their frailty and vulnerability to falls, fractures, and infections.34
Fortunately, supplementing with probiotic bacteria can help alleviate the digestive issues that can occur as a result of microbial imbalance.
Easing Abdominal Symptoms with Probiotic Bacteria
Beneficial bacteria are essential for maintaining proper balance among the trillions of organisms living in the intestines. Low growth of the “good guys” can lead to overgrowth and imbalance of organisms less directly beneficial (and some directly harmful) to the body’s health.
Studies show that probiotic organisms (which are cultures of living beneficial bacteria) can help reduce abdominal symptoms and promote healthy intestinal function by promoting their own and other beneficial organisms’ growth and suppressing that of less useful bacteria.35,36
The MTCC 5856 strain of Bacillus coagulans (formerly known as Lactobacillus sporogenes) is especially beneficial because it is coated in a tough outer layer that resists digestion in the stomach and small intestine.35,37 This allows it to be delivered intact to the large intestine, where it can then “hatch” out to set up new colonies in a sustainable fashion.35,37,38
It takes an estimated four hours from ingestion to germination in the intestine. However, over time, it is gradually excreted and needs to be replenished with fresh supplementation.36,37
Once established, B. coagulans produces lactic acid, which is a useful chemical that helps suppress the growth of disease-causing bacteria and promotes its own growth.35,37,38 Lactic acid bacteria are commonly used as “starter cultures,” in fermented foods such as yogurt, kimchi, sauerkraut, kefir, sourdough bread, pickles, and many other healthful foods.35 Furthermore, production of lactic acid is the result of the presence of lactase, the digestive enzyme that breaks down lactose, and is missing in so many adults.37,39
B. coagulans also produces bacteriocins, which are compounds that help maintain a healthy balance of bacteria by limiting the growth of less desirable bacteria.35,37
The value of this resilient B. coagulans strain of bacteria has been shown in studies of people with gastrointestinal issues, such as chronic constipation, chronic diarrhea, and irritable bowel syndrome.
A study of people with chronic constipation showed that 70% of subjects had improvement in abdominal distension and normalization of stools following supplementation with 300 to 750 million spores of B. coagulans per day for up to 10 days.37
A study of patients with acute or chronic diarrhea demonstrated, in a randomized fashion, that probiotic supplementation with either B. coagulans or another commonly used organism called Bifidobacterium longum produced good relief from symptoms.
Irritable bowel syndrome (IBS) is a common and difficult-to-treat condition that can cause diarrhea and constipation, along with significant abdominal discomfort, gas, and bloating. In a multi-center, randomized, double-blind controlled study of IBS patients, daily supplementation with tablets containing 2 billion spores of B. coagulans was found to significantly reduce symptom scores, abdominal discomfort scores, stool quality, and physicians’ overall assessment scores.40 Additionally, the patients receiving the probiotic bacteria showed improvement in bloating, vomiting, diarrhea, abdominal pain, and stool frequency, compared with control subjects.
The digestive tract changes with age. The amounts of digestive enzymes the body produces decline over time, leaving undigested food molecules free to pass into the colon where they ferment and produce noxious gas, bloating, cramping, and diarrhea.
Adding to this challenge, the body’s normally helpful tenants, the microbes living in the colon, become disruptive and imbalanced, potentially invading the small intestine where they can produce inflammation and poor digestion.
In human studies, supplemental digestive enzymes have provided increased digestive comfort and reduction in common symptoms of indigestion. And supplementation with probiotic B. coagulans bacteria not only boosts the population of good bacteria, but also results in production of natural bacterial compounds that suppress less beneficial, or even overtly harmful, bacteria. These changes have been demonstrated to improve after-meal comfort while restoring the natural balance of organisms in the intestinal tract.
For those troubled by bloating, cramps, gas, loose stools, or other digestive symptoms following a normal meal, restoring normal enzymes and intestinal microbial population could help alleviate after-meal distress.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
- Taylor J, Landry E, Lalonde L, Tsuyuki RT. Results of a national survey on over-the-counter medicines, Part 1: Pharmacist opinion on current scheduling status. Can Pharm J (Ott). 2012; 145(1):40-4.
- Sheen CL, Colin-Jones DG. Review article: over-the-counter drugs and the gastrointestinal tract. Alimen Pharmacol Ther. 2001;15(9):1263-70.
- Van Vliet EP, Kuipers EJ, Steyerberg EW, Siersema PD. Users and utilization patterns of over-the-counter acid inhibitors and antacids in The Netherlands. Scand J Gastroenterol. 2008;43(6):662-8.
- Available at: http://goo.gl/kyZrkD. Accessed August 6, 2013.
- Farges MC, Vasson MP, Davot P, et al. Supplementation of oral nutrition with pancreatic enzymes improves the nutritional status of aged endotoxemic rats. Nutrition. 1996;12(3):189-94.
- Available at: http://goo.gl/JttyqX. 2008. Accessed August 6, 2013.
- Di Stefano M, Veneto G, Malservisi S, Strocchi A, Corazza GR. Lactose malabsorption and intolerance in the elderly. Scand J Gastroenterol. 2001;36(12):1274-8.
- Baum BJ, Levine RL, Kuyatt BL, Sogin DB. Rat parotid gland amylase: evidence for alterations in an exocrine protein with increased age. Mech Aging Dev. 1982;19(1):27-35.
- Laugier R, Bernard JP, Berthezene P, Dupuy P. Changes in pancreatic exocrine secretion with age: pancreatic exocrine secretion does decrease in the elderly. Digestion. 1991;50(3-4):202-11.
- Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010;16(24):2978-90.
- Kirsch M. Bacterial overgrowth. Am J Gastroenterol. 1990;85(3):231-7.
- Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292(7):852-8.
- Vitetta L, Manuel R, Zhou JY, Linnane AW, Hall S, Coulson S. The overarching influence of the gut microbiome on end-organ function: the role of live probiotic cultures. Pharmaceuticals (Basel). 2014;7(9):954-89.
- Vellas B, Balas D, Moreau J, et al. Exocrine pancreatic secretion in the elderly. Int J Pancreatol. 1988;3(6):497-502.
- Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73.
- Friess H, Michalski CW. Diagnosing exocrine pancreatic insufficiency after surgery: when and which patients to treat. HPB (Oxford). 2009;11 Suppl 3:7-10.
- Dominguez-Muñoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Gastroenterol Hepatol. 2011;7(6):401-3.
- Eun JS, Beauchemin KA. Effects of a proteolytic feed enzyme on intake, digestion, ruminal fermentation, and milk production. J Dairy Sci. 2005;88(6):2140-53.
- Omogbenigun FO, Nyachoti CM, Slominski BA. Dietary supplementation with multienzyme preparations improves nutrient utilization and growth performance in weaned pigs. J Anim Sci. 2004;82(4):1053-61.
- Knill-Jones RP, Pearce H, Batten J, Williams R. Comparative trial of Nutrizym in chronic pancreatic insufficiency. BMJ. 1970;4(5726):21-4.
- Griffin SM, Alderson D, Farndon JR. Acid resistant lipase as replacement therapy in chronic pancreatic exocrine insufficiency: a study in dogs. Gut. 1989;30(7):1012-5.
- Suarez F, Levitt MD, Adshead J, Barkin JS. Pancreatic supplements reduce symptomatic response of healthy subjects to a high fat meal. Dig Dis Sci. 1999;44(7):1317-21.
- Misselwitz B, Pohl D, Fruhauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterol J. 2013;1(3):151-9.
- Kuhn RJ, Gelrud A, Munck A, Caras S. CREON (Pancrelipase Delayed-Release Capsules) for the treatment of exocrine pancreatic insufficiency. Adv Ther. 2010;27(12):895-916.
- Park S, Johnson MA. What is an adequate dose of oral vitamin B12 in older people with poor vitamin B12 status? Nutr Rev. 2006;64(8):373-8.
- Sanders SW, Tolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactose-intolerant subjects. Clin Pharm. 1992;11(6):533-8.
- Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-1119.
- De Vos WM, de Vos EA. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr Rev. 2012;70 Suppl 1:S45-56.
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Letting the kids drink is a tough subject for parents: To give a tipple or not?
People who take calcium supplements may be at increased risk for developing buildups of plaque in their arteries, which is a sign of heart disease, a new study found.However, people who consume a lot of calcium through the food they eat may actually be at a lower risk of heart disease, the study showed.The findings add to a growing body of evidence that some dietary supplements, such as calcium supplements, may have harmful effects.”When it comes to using vitamin and mineral supplements, particularly calcium supplements being taken for bone health, many Americans think that more is always better,” study co-author Dr. Erin Michos, associate director of preventive cardiology at the Johns Hopkins University School of Medicine in Baltimore, said in a statement. “But our study adds to the body of evidence that excess calcium in the form of supplements may harm the heart and vascular system.”In the study, the researchers analyzed information from more than 2,700 people ages 45 to 84, who answered questions about their calcium intake, from both their diets and supplements.More From LiveScience 7 foods you can overdose on 7 foods your heart will hate Top 10 amazing facts about your heart 9 good sources of disease-fighter vitamin DThe participants also underwent two CT scans, one at the beginning of the study and another 10 years later. The scans looked for plaques containing calcium in the arteries of the heart, which are the coronary arteries. The presence of such calcium-containing plaques means that a person is at increased risk of developing heart disease, or having a heart attack. At the start of the study, about 1,500 people did not have any calcium-containing plaques in their arteries.The researchers then divided people into five groups based on the individuals’ calcium intake from both their diets and supplements.The people with the highest intake of calcium (greater than 1,400 milligrams per day) were actually 27 percent less likely to develop calcium-containing plaques in their coronary arteries over the 10-year study, compared with the group with the lowest intake of calcium (less than 400 mg per day). Moreover, the people in the highest-intake group who achieved their high calcium intake without supplements were at an especially low risk of developing plaques, according to the study.In contrast, people who took calcium supplements were overall 22 percent more likely to develop calcium-containing plaques over the study period, compared with those people who didn’t use such supplements. Forty-six percent of people in the study used calcium supplements.It’s possible that large doses of calcium consumed in supplements may temporarily elevate calcium levels in the blood, which leads to calcifications in blood vessels, the researchers said.”There is clearly something different in how the body uses and responds to supplements versus intake through diet that makes it riskier,” said study co-author John Anderson, a professor emeritus of nutrition at the University of North Carolina at Chapel Hill. “It could be from taking a large dose all at once that the body is unable to process.”The researchers noted that they found only an association and cannot prove that taking calcium supplements causes an increase in the risk of developing calcium-containing plaques and heart disease. In addition, the participants self-reported their calcium intake, and it’s possible they did not always remember their intake correctly, which could affect the results, the researchers said.Previous research supports the new study’s results, though. A 2012 study from Sweden found that consuming high amounts of calcium was linked with an increased risk of dying from any cause during the study period, including from heart disease.The researchers said their new results are “hypothesis generating” and should spur more research in this area.”Based on this evidence, we can tell our patients that there doesn’t seem to be any harm in eating a heart-healthy diet that includes calcium-rich foods, and it may even be beneficial for the heart,” Michos said. “But patients should really discuss any plan to take calcium supplements with their doctor to sort out a proper dosage or whether they even need” such supplements.The study was published Oct. 11 in the Journal of the American Heart Association.Original article on Live Science.
The digestive tract of the ‘future of food’ does not always run smooth… The startup behind drink-your-dinner powder Soylent has issued a product recall. Not..
Life Extension Benefits of Methionine Restriction
by Ben Best
- METHIONINE BASICS
- METHIONINE RESTRICTION EFFECTS
- METHIONINE RESTRICTION FOOD DATA
- METHIONINE RESTRICTION DIET
Methionine is the only essential amino acid containing sulfur. Methionine is the precursor of the other sulfur-containing amino acids: cysteine, taurine, homocysteine, and cystathione. Methionine is essential for the synthesis of proteins and many other biomoleules required for survival. Rats fed a diet without methionine develop fatty liver disease which can be corrected by methionine supplements [DIGESTIVE DISEASES AND SCIENCES; Oz,HS; 53(3):767-776 (2008)]. Dietary methionine is essential for DNA methylation. Reduced DNA methylation results in genetic instability, aberrant gene expression, and increased cancer.
The above paragraph is the first paragraph from the section on methionine in my article dealing with the Methionine Cycle. Material in that article is useful background for the information below. Note, however, that there is an inverse correlation between lifespan and the methionine content of protein in the heart muscle of eight mammalian species [MECHANISMS OF AGEING AND DEVELOPMENT; Ruiz,MC; 126(10):1106-1114 (2005)]. The sulfur-containing amino acids methionine and cysteine are the most readily oxidized of any of the amino acids — both as free amino acids or in proteins. Methionine is oxidized to methionine sulfoxide, but methionine sulfoxide reductases enzymatically regenerate methionine [BIOPHYSICA ET BIOCHEMICA ACTA; Lee,BC; 1790 (11): 1471-1477 (2009)].
Substantial evidence indicates that as much as half of the life-extension benefits of CRAN (Calorie Restriction with Adequate Nutrition) are due to restriction of the single amino acid methionine. In a study of rats given 20% the dietary methionine of control rats, mean lifespan increased 42% and maximum lifespan increased 44% [THE FASEB JOURNAL;Richie,JP; 8(15):1302-1307 (1994)]. Blood glutathione levels were 81% higher in the methionine-restricted rats at maturity, and 164% higher in old age. In other studies, methionine-restricted rats showed greater insulin sensitivity and reduced fat deposition [AMERICAN JOURNAL OF PHYSIOLOGY; Hasek,BE; 299:R728-R739 (2010) and AGING CELL; Malloy,VL; 5(4):305-314 (2006)].
An experiment on mice given 35% the methionine of controls showed only a 7% increase in median life span [JOURNALS OF GERONTOLOGY; Sun,L; 64(7):711-722 (2009)]. Another mouse study showed lowered serum insulin, IGF−1, glucose, and thyroid hormone for methionine at one-third the normal intake. There was significant mouse mortality for methionine less than one-third normal intake, but with one-third intake of methionine maximum lifespan was significantly increased [AGING CELL; Miller,RA; 4(3):119-125 (2005)]. Rats generally show greater longevity benefits from CRAN than mice.
Mitochondrial free radical generation is believed by many biogerontologists to be a significant contributor to aging damage. Rats given 20% the dietary methionine of control rats show significantly decreased free radical generation from complex I and complex III of liver mitochondria as well as from complex I of heart mitochondria — associated with reduced oxidative damage to mitochondrial DNA and protein [THE FASEB JOURNAL;Sanz,A; 20(8):1064-1073 (2006)]. These results are comparable to the reduced mitochondrial free radical generation seen in CRAN rats [ENDOCRINOLOGY; Gredilla,R; 146(9):3713-3717 (2005)]. Rats given 60% rather than 20% of the methionine of control rats showed nearly the same amount of reduced mitochondrial free radical generation and damage [BIOCHEMICA ET BIOPHYSICA ACTA; Lopez-Torres,M; 1780(11):1337-1347 (2008)]. Body weight was not reduced with 60% dietary methionine, leading to the conclusion that such reduction would not result in reduced growth in children [REJUVENATION RESEARCH; Caro,P; 12(6):421-434 (2009)]. It was concluded that methionine restriction is the sole reason for reduced mitochondrial free radical generation and damage associated with CRAN [Ibid.] and protein restriction [BIOGERONTOLOGY; Caro,P; 9(3):183-196 (2008)].
Evidence for the suggestion that methionine oxidation plays a significant role in lifespan can be found in the considerable lifespan extension benefits seen in transgenic fruit flies that overexpress a gene for repairing oxidized methionine in protein [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Ruan,H; 99(5):2748 (2002)]. The sulfur-containing amino acids methionine and cyteine are more easily oxidized in proteins than other amino acids [JOURNAL OF PHYSIOLOGY)], which is apparently related to the reduced free radical generation in mitochondria seen in methionine restriction. Both the fruit fly experiment and the methionine restriction experiments indicate a significant impact on lifespan from methionine oxidation.
It has been suggested that glycine supplementation has the same effect as methionine restriction. An experiment with glycine supplementation in rats showed a 30% extension in maximum lifespan [FASEB JOURNAL; Brind,J; 25:528.2 (2011)]. Additionally, three grams of glycine daily has been shown to improve sleep quality in young (average age 31) female Japanese adults [SLEEP AND BIOLOGICAL RHYTHM; Inagawa,K; 4:75-77 (2006)]
The adjoining table (my Table 1) from [AMERICAN JOURNAL OF CLINICAL NUTRITION; Young,VR; 59(suppl):1203s-1212s (1994)] indicates the essential amino acids most likely to be limited in plant protein foods. Cereal protein contains comparable sulfur-containing amino acids (including methionine) per gram as animal foods, whereas fruit and legume protein contain about 65% as much methionine. Nuts and seeds are particularly high in methionine, on average 20% higher in methionine than animal protein, although the absolute amount of protein in animal foods tends to be higher, which makes total methionine intake generally higher in animal foods. Vegetables are not shown in Table 1, but as described in Table 4 in the AMERICAN JOURNAL OF CLINICAL NUTRITION paper from which Table 1 is taken, vegetables are on average in the 1-2% range for percent protein and fruits are in the 0.5-1% protein range — so neither fruits nor vegetables should be considered serious sources of protein (green peas are an exceptional vegetable with 5.4% protein, and avacado is an exceptional fruit with 2% protein). Cereals are typically 7-13% protein and legumes are typically 20-30% protein (soybeans are exceptionally high in protein even for legumes, being in the range of 35-45% protein).
The dry weight of beef, broccoli, peanuts, and peas is about one-third protein, whereas cereals and fruits are less than 10% dry weight protein. Unlike many other plant proteins, legumes are not particularly low in lysine, and they are close to animal protein in threonine content. Vegetarians attempting to achieve complete protein often combine cereals (which are relatively high in methionine for plant protein) with legumes (which are relatively high in lysine for plant protein).
Lentils and other beans contain high amounts of phytic acid (phosphate-rich inositol), which can chelate positively-charged multivalent mineral ions (especially iron, zinc, magnesium, and calcium), preventing absorption. Soaking lentils and beans in warm water overnight not only makes them easier to cook, it allows some of the phytates to be soaked-out (and thrown-away with the water). Acidic solution (such as vinegar) better removes the phytates. Cooking also helps destroy phytates.
Although it would be very difficult to determine a diet providing optimum methionine for maximum human lifespan — even on the basis of rat experiments — evidence is convincing that reducing dietary methionine can help extend lifespan. The Table 2, listing milligrams of methionine per 100 grams of food (rather than per gram of protein, as in Table 1), could be helpful. Table values are based on [FOOD VALUES OF PORTIONS COMMONLY USED by Jean Pennington (1989)].
The absolute methionine content of a food is better evaluated knowing what the water, fat, carbohydrate, fiber, and protein content of that food is. A higher protein content and a lower methionine content is better than having a low methionine content because the food is low in protein and high in water, fat, or carbohydrate. Lima beans and rice are relatively high in both carbohydrate and methionine. Onions and strawberries are low in methionine, but are high in water and low in protein.
The data for Table 3 is taken from [NUTRITIVE VALUE OF FOODS; USDA Bulletin 72 (1981)], but is adjusted to give percent protein by dry weight. Percent water in the food is not related to the other columns. Fiber content is not given, and I suspect that fiber is equated with carbohydrate. I may have made a few errors, and I suspect that the data contains a few errors (garbage-in, garbage-out). But for the most part I think the data is good, my transcription is accurate, and my calculations are correct.
Brown rice would be more nutritious than white rice, except that the fats in germ that is removed to make white rice can go rancid. Ingestion of Advanced Glycation End-Products (AGES) is detrimental to health.
Table 4gives the percent fat obtained for selected items in the above table, and breaks down the fat into percent saturated, monosaturated, and polyunsaturated fat. Numbers are rounded to the nearest whole number, which is why the total percentages don’t always add to 100. Monosaturated fats and polyunsaturated fats are preferred to unsaturated fats except where there is rancidity. Again, ingestion of Advanced Glycation End-Products (AGES) is detrimental to health. I had no data for non-fat cheese, the only kind of cheese that I eat.
Table 5 gives relative proportions of all of the essential amino acids (plus tyrosine) for some representative high-protein animal foods as well as for some low-methionine plant foods.
Lysine is given after methionine because lysine is most often the limiting amino acid (the essential amino acid found in the smallest quantity relative to requirement) in cereals, nuts, and seeds — but lysine in abundant in legumes, for which methionine is typically the limiting amino acid [AMERICAN JOURNAL OF CLINICAL NUTRITION; Young,VR; 59(suppl):1203s-1212s (1994)]. Lysine is therefore listed second in the table. Leucine is listed third because of its paradoxical ability to reduce fat in high doses [DIABETES; Zhang,Y; 56(6):1647-1654 (2007)] and low doses [DIABETES; Cheng,Y; 59(1):17-25 (2010)]. Leucine and threonine are the limiting amino acid in vegetables and fruits, although vegetables and fruits are too low in protein to be considered significant proteins sources. Trytophan restriction has been shown to have a modest (compared to methionine restriction) ability to extend lifespan in rats [ MECHANISMS OF AGEING AND DEVELOPMENT; Ooka,H; 43(1):79-98 (1988)], reputedly by opposing an age-related increase in brain serotonin.
Tyramine was evaluated because of claims that high dietary tyramine could have adverse reactions with monoamine oxidase inhibitors (I take deprenyl). But none of the foods listed have seriously high levels of tyramine, so tyramine is not really a concern.
Again, this data is taken from [FOOD VALUES OF PORTIONS COMMONLY USED by Jean Pennington (1989)]. I have adjusted the Pennington data to be standardized for 100 grams of food, rather than reproducing the variable quantities of food given, which makes comparison difficult. I may have made transcription errors, but probably not many (if any).
Confusion can be caused by the variable amounts of proteins in the foods. Some foods have high water content (such as onion), or high carbohydrate content (such as rice), or high fat content (such as nuts). To compare relative amounts of methionine in the proteins in the foods, I have created Table 6 in which I have adjusted the values to reflect milligrams of amino acid per gram of protein, rather than the per 100 grams of food used in the previous table. To do this, I first calculate dry weight [(100 − % water) / 100] and then divide by % protein. (Note that Persian/English walnuts contain 60% the protein of black walnuts, mostly because of higher fat content. This creates a misimpression that Persian/English walnuts are much lower in methionine than black walnuts.)
I make no guarantee that I have made no transcription errors in manually copying data from either table to my calculator.
I am searching for foods that are high in protein, but low in methionine, as a source of protein. Preferably the foods should be high in the essential amino acids (other than methionine), and low in fat (especially saturated fat) and low in carbohydrate. As sources of protein, the data in the Table 6 are important in proportion to the percent protein in the food, especially when the water content is low. As long as protein is adequate in the diet overall, other foods that are low in protein and high in water are not much of a concern from a methionine restriction point of view. Legumes offer the best tradeoff of low methionine, and high protein (high essential amino acids), particularly lentils and pinto beans. Adzuki beans would be a contender except that the high fiber content makes them hard to process. I prefer to get my fiber from other sources.
Table 7 was created by dividing methionine amount into the amounts of the other essential amino acids shown in Table 5. Thus, the numbers in the lysine column reflect how many times the lysine content of the food exceed the methionine content.
Pinto beans and lentils are the high-protein foods that show the best low-methionine, high-lysine profile, by a large margin. Lentils, however, are easier to soak before cooking to remove phytates, and produce a bit less odiferous flatulance than pinto beans. Both legumes, however, are high in phytic acid and raffinose oligosaccharides. Humans lack the enzyme to digest raffinose, which passes to the lower intestine where bacteria possessing the digestive enzyme create gases which can be quite odiferous.
Soaking pinto beans for 16 hours at room temperature only reduces raffinose oligosaccharides by 10%, and 90 minutes of cooling only cuts the raffinose oligosaccharide content in half [JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY; Song,D; 54(4):1296-1301 (2006)].
Just as the objective of calorie restriction is not to live without calories, methionine is an essential amino acid that can be reduced to 60% normal consumption to obtain most of the benefit [BIOGERONTOLOGY; Caro,P; 9(3):183-196 (2008)]. That dietary objective can be met without the need to consume legumes.
Vegan mom fed her 11-month-old only fruit and nuts. Now she faces child endangerment charges. – The Washington PostAuthor: SupremePundit
She was proud to be a vegan and wanted her son to live like she did. But her family members said she took her food choices too far — her diet became a danger, in their eyes, something closer to an obsession than a healthy lifestyle.
“She was going to live on water and sunlight,” her sister-in-law told CBS Pittsburgh.
When the 33-year-old woman from western Pennsylvania, Elizabeth Hawk, began feeding her 11-month-old child sparse meals of only fruit and nuts, however, that was beyond the pale.
The boy developed what the sister-in-law, Brandy Hawk, described as a severe rash. He seemed to have lost control of his motor skills, she said, rendering his hands useless. Elizabeth Hawk said allergies were the reason for his apparent malaise, not the diet.
That argument did not convince Jerry Hawk, Elizabeth’s separated husband and the father of the child. He removed his son from his estranged wife’s care, taking the boy to a Children & Youth Services agency in nearby Fayette County. From there, reported Philly.com, the agency took the child to a hospital in West Virginia.
An attending physician said the lack of nutritious food, according to Pennsylvania’s WKBN, caused a “failure to thrive.” Malnourishment had hindered the boy’s ability to develop, and ignoring the skin condition could have led to septic shock.
It is not inevitable that a vegan-only menu would doom young children to sickness or starvation, as The Washington Post wrote in July. But a commitment to veganism can make raising a healthy child more challenging, as parents must ensure that a child ingests sufficient calories and the correct balance of nutrients. In 2001, for instance, a pair of vegetarian nutritionists published recommendations for vegan infants in the Journal of the American Dietetic Association:
“For the first 4 to 6 months, breast milk should be the sole food with soy-based infant formula as an alternative. Commercial soymilk should not be the primary beverage until after age 1 year. Breastfed vegan infants may need supplements of vitamin B-12 if maternal diet is inadequate; older infants may need zinc supplements and reliable sources of iron and vitamins D and B-12. Timing of solid food introduction is similar to that recommended for non-vegetarians. Tofu, dried beans, and meat analogs are introduced as protein sources around 7-8 months. Vegan diets can be planned to be nutritionally adequate and support growth for infants.”
The young boy now lives with his father. Brandy Hawk, the sister-in-law, told CBS Pittsburgh the child is “doing great” and has “turned completely around.”
Elizabeth Hawk faces charges of child endangerment and was released on her own recognizance. A preliminary hearing has been set for Nov. 14, Philly.com reported.
The researchers found that the people with Crohn’s disease had significantly higher levels of two types of bacteria, called Escherichia coli and Serratia marcescens, and one fungus, called Candida tropicalis, compared with their healthy relatives and the other people in the study who did not have the disease, according to the study, published Sept. 20 in the journal mBio.Although previous research in mice has suggested that this fungus may be involved in Crohn’s, this is the first time it has been linked to the condition in people, the researchers said.Moreover, when the researchers examined these bacteria and fungus, they found that the three microorganisms worked together to form a so-called biofilm — a thin, sticky layer of microorganisms — that attaches itself to a portion of the gut. This biofilm could trigger the inflammation that causes the symptoms of Crohn’s disease, the researchers said. [5 Ways Gut Bacteria Affect Your Health]The new study “moves the field forward,” said Dr. Arun Swaminath, director of the inflammatory bowel disease program at Lenox Hill Hospital in New York City, who was not involved in the study. “The really neat thing they have done is to show how [these microorganisms] actually interact together,” to form the biofilm, he said.However, the study was conducted in a small group of patients in France and Belgium, and more research is needed to see if these findings would apply to patients in other countries, Swaminath said.Originally published on Live Science.Editor’s Recommendations Body Bugs: 5 Surprising Facts About Your Microbiome The Poop on Pooping: 5 Misconceptions Explained 8 Tips to Be a Probiotic Pro
The opinions voiced in this material are for general information only and are not intended to provide specific advice or recommendations to any individual. For your individual planning and investing needs, please see your investment professional.
Jonathan DeYoe has been a financial advisor in San Francisco for the past two decades, giving him a first-row seat to the unprecedented explosion of wealth creation ushered in by tech industry. Here are his 10 best pieces of money advice.
1. Put your money where your happiness is.
It is an incredible understatement to say the San Francisco Bay Area is an expensive place to live. Whether you come from money or just joined Facebook, you will have to make trade-offs to keep your head above water here — make the tradeoffs that are appropriate for you.
You don’t have to drive a Tesla, you aren’t required to live in a rad pad in the Mission, and you don’t need designer duds or the newest iGadget. Give up the trappings of success that hold no personal meaning for you and focus your financial resources on activities and affordable luxuries that build your particular brand of happiness, like a rock-climbing course and killer burritos.
2. Invest in yourself early and often.
If you are an engineer or scientist, you must stay on top of your technical game, but don’t hesitate to spend money on coaching or classes to develop your communication and leadership skills, as well.
If you are a professional, constantly hone your craft. Read broadly within your industry, enroll in continuing education, obtain advanced professional designations, and find opportunities to network with new people.
The dollars you dedicate to increasing your intellectual capacity and enhancing your ability to work well with others can boost your income substantially. Lifelong learning and professional development both lead to long-term success. The sooner you embark upon rigorous self-improvement, the longer you’ll enjoy the fruits of your labors, so invest in yourself now.
3. Don’t count your chickens before they’re hatched.
Equity compensation in the form of RSUs and stock-options can be a wonderful addition to your income and asset base. Over the years, I have seen many folks become wealthy through their company stock programs.
However, I have watched just as many stock compensation packages go up in smoke. Never forget that your stock has NO real value until you are fully vested and someone is willing to give you cash money for it on the open market. Just because a VC gives your company a sky-high valuation does not mean you’ll receive that valuation if (not when) the stock ever trades publicly.
Do not borrow against your stock. Do not pledge your stock as collateral to buy a massive house on Russian Hill. Do not count your stock among your REAL assets until it is actually part of your real assets. Better yet, don’t even count the eggs in your basket until you’ve hatched and sold them.
4. Get your foot in the front door.
Yes. The cost of housing in the Bay Area is ridiculous! When I read a 2015 San Francisco Chronicle article claiming that a Mountain View, California, resident was renting a tent in their backyard with bathroom access but no kitchen privileges for $900, I knew that we had all gone off the deep-end.
Today the median sales price for San Francisco homes is over $1.1 Million! No one is happy about real estate prices in the greater Bay Area, but if you are planning to stay here for five to seven years or more, consider buying a home. It doesn’t have to be beautiful or close-in. Alameda and Contra Costa counties are still relatively affordable. Just get your foot in the front door.
If you stay on the sidelines, don’t be surprised if the market continues to run away from you. Expect rare short-term dips, like we saw in 2008-2009, to effervesce quickly due to decades of housing policy that limited building.
And while many cities have strong rent-control laws, remaining a renter means your housing costs will continue to grow — perhaps pricing you out of the rental market and into that tent in someone’s backyard.
5. Turn a passion into a side hustle into a business.
First and foremost, do not neglect your day job. If your 9-to-5 office gig pays the bills and affords you ample pocket money, pursuing your passion for cooking by taking a second job as a sous-chef in a neighborhood restaurant won’t help you get ahead. You will burn out.
Nonetheless, there are hundreds of creative ways to capitalize on your hidden and not so hidden talents. My 11-year-old son bakes pies for neighbors, cat sits, and walks dogs. If you like baking or pets, why not?
You prefer to drive? Try Lyft or Uber. You love to write? Start a blog and learn how to drive traffic with social media. You’re a crack web designer? Register on freelance sites like Upwork or. You have a spare bedroom? You get the idea!
6. Create a financial road map.
Where do you want to go in life? As with any journey, if you have a specific destination in mind, you will need to take specific steps to get there. Planning your route is essential.
No one can afford to experience everything they want, but you can accomplish what is most important to you by creating a financial road map. Decide what tradeoffs you’re willing to make to achieve your goals. Take staycations until you’ve saved the down payment on a new house? Live with your old car six more months so that you can afford that new motorcycle next year? Drive Uber on week-ends to cover the cost of coding classes?
Where are you now? In debt? $20,000 away from that down payment? Underemployed? No need for shame. Accept your today and plan for a better tomorrow. What tradeoffs will you make? How much do you need to save? How are you going to get where you want to be? Planning makes things happen for you! NOT planning lets them happen to you.
7. Make your health a priority.
There are actually significant financial benefits to being healthy.
It probably comes as no surprise that healthier people have higher energy levels, improved resistance to illness, improved moods, higher self-esteem, better brain function, reduced fatigue, and less anxiety. But research indicates that healthier people may earn more and spend less, as well.
Good health while you’re young gives you the energy and focus to work harder and smarter, which can lead to better raises and more promotions, which translates into increased lifetime earnings. And good health later in life means fewer doctors visits, fewer medications, and hopefully decreased long-term care expenses as you age.
8. Save at least 10% of every dime you make.
Or, as the familiar saying goes, “Pay yourself first.”
Once you got your first “real” job and started earning more, you probably started spending more, too. If that trend continues every time you get a promotion or better job, you will never get ahead. At some point, you must make a conscious decision to save a specific portion of your income every single month. These savings will form the foundation upon which your entire financial life can be built.
Start by saving at least 10% of your gross salary every paycheck, and increase your savings 1% each year until you are saving 20% of your income. Use those initial savings to establish a cash emergency fund with six months to two years of living expenses. At the same time, take advantage of the tax breaks and “free” money you get from participating in your company’s 401(k) matching program. Next, pay-off your high interest debt. Then max out your 401(k), ROTH, and IRA combo, after consulting with your tax professional. The final step is to save even more in a taxable investment account and/or pay down your low interest debts.
9. Invest 90% of your liquid assets in an appropriately allocated, broadly diversified, and annually rebalanced basket of publicly traded securities.
I expect I will get some healthy Bay Area blow-back for this statement: Your investing prowess will not lead to “outperformance” in the long run.
Timing the markets, stock selection, and economic predictions may be an enduring part of the investment landscape, but none of those strategies offer a repeatable process for financial success. Luck often plays a much bigger role than skill when it comes to investment performance.
There is plenty of research on portfolio construction available to anyone willing to look. There is no evidence to support the idea that recent past performance will persist into the future or that folks dedicated to the timing and selection have been or will be successful doing so. Stock-picking requires repeated luck. Asset allocation, diversification, and rebalancing rely on something we can control, our consistent behavior, patience, and discipline.
10. Always be mindful of the big picture.
The course of human social and economic history expresses itself in a very long upward trend. That upward trend is often punctuated by short-term market upheavals, which are amplified by Wall Street and the financial press.
Stock markets and the financial media constantly over-correct in both directions in a seemingly endless cycle. Upside yields to downside. Excitement leads to despair. The good news? Today’s losses sow the seeds of future gain. You can’t consistently predict short-term outcomes because the economic and market details are ever-changing. Nonetheless, the big picture remains the same. Instead of reacting and over-reacting to the markets whims, be mindful of the big picture and stick to your thoughtfully constructed investment program and financial plan.
Jonathan K. DeYoe, AIF and CPWA, is the author of Mindful Money: Simple Practices for Reaching Your Financial Goals and Increasing Your Happiness Dividend. He is the founder and president of DeYoe Wealth Management in Berkeley, California, and blogs at the Happiness Dividend Blog. Financial planning and investment advisory services offered through DeYoe Wealth Management, Inc., a registered investment adviser.
Children and teenagers who are obese have different microorganisms living in the digestive tract than their lean counterparts
Childhood obesity has reached epidemic proportions in the United States and is rapidly increasing among industrialized nations. According to the U.S. Centers for Disease Control and Prevention, obesity rates have more than doubled in children and quadrupled in adolescents in the past 30 years. Obesity affects 17% of children and teens nationwide, and in 2012 alone more than one-third of children and adolescents were classified as overweight or obese. Moreover, obesity is associated with an estimated $14.1 billion in additional prescription drug, emergency room visit, and outpatient visit costs each year, according to the Endocrine Society’s Facts and Figures Report.
Now, a new study led by researchers at Yale University has found a connection between gut microbiota and fat distribution in children and teenagers. The investigators found that children and adolescents who were obese had different microorganisms living in their digestive tract than their lean counterparts.
“Our findings show children and teenagers with obesity have a different composition of gut flora than lean youth,” explained senior study investigator Nicola Santoro, M.D., Ph.D., associate research scientist in the department of pediatrics at Yale University. “This suggests that targeted modifications to the specific species composing the human microbiota could be developed and could help to prevent or treat early-onset obesity in the future.”
The findings from this study were published recently in the Journal of Clinical Endocrinology & Metabolism in an article entitled “Role of Gut Microbiota and Short Chain Fatty Acids in Modulating Energy Harvest and Fat Partitioning in Youth.”
The Yale team managed to examine the gut microbiota and weight in 84 children and teenagers who were between 7 and 20 years old. The participants included 27 youth who were obese, 35 who were severely obese, 7 who were overweight, and 15 who were healthy weight. Researchers analyzed the participants’ gut microbiota. The participants underwent magnetic resonance imaging (MRI) to measure body fat partitioning, provided blood samples, and kept a 3-day food diary.
The researchers discovered eight groups of gut microbes that were linked to the amount of fat in the body. Four of the microbial communities tended to flourish in children and teens with obesity compared to their normal-weight counterparts. Additionally, smaller amounts of the other four microbial groups were found in participants who were obese compared to children and teenagers of normal weight. The gut microbiota found in youth who were obese tended to be more efficient at digesting carbohydrates than the gut flora of teenagers and children of normal weight. “A significant association was found between the Firmicutes to Bacteroidetes ratio, and the abundance of Bacteroidetes and Actinobacteria with body mass index, visceral and subcutaneous (SC) fat,” the authors wrote. “Plasma acetate, propionate, and butyrate were associated with body mass index and visceral and SC fat and with hepatic de novo lipogenesis. Moreover, the rate of carbohydrate fermentation from the gut flora was higher in obese than in lean subjects.”
Also, the children with obesity tended to have higher levels of short-chain fatty acids in the blood than children of normal weight. The study found short-chain fatty acids, which are produced by some types of gut bacteria, are associated with the production of fat in the liver.
“Our research suggests that short-chain fatty acids can be converted to fat within the liver and then accumulate in the fat tissue,” Dr. Santoro remarked. “This association could signal that children with certain gut bacteria face a long-term risk of developing obesity.”
One Of The World’s Top Aging Researchers Has A Pill To Keep You Feeling Young | Co.Exist | ideas + impactAuthor: SupremePundit
There are also natural compounds that elevate sirtuins—one is resveratrol, which is already sold as a dietary supplement today. Another is called NAD. NAD—Nicotinamide adenine dinucleotide—is one of the most compelling bits of chemistry related to aging. Its presence in the body is directly correlated with the passage of time: An elderly man will have about half the levels of NAD is his body as a young person. There’s no amount of healthy eating or exercise that can stop the decline. But in a scientific
If a restaurant charged you $40 for coffee. Surely you’d be upset. But you let hospitals do it to you all the time.
It turns out that hospitals inflate specific prices in ways that aren’t transparent to the patient, according to a new study that appeared Sept. 7 2016 in the journal Health Affairs.
Researchers at Johns Hopkins University in Baltimore found that many hospitals charged more than 20 times the cost of some services, particularly for certain services like CT scans and anesthesiology. The researchers said that the pattern of charging suggests that hospitals strategically look for surreptitious ways to boost revenue.
“Hospitals apparently mark up higher in the departments with more complex services, because it is more difficult for patients to compare prices in these departments,” Ge Bai, who led the study and is an assistant professor at the Johns Hopkins Carey Business School, said in a statement. [7 Medical Myths Even Doctors Believe]
Other high-tech services with exorbitant markups include MRI, electrocardiology (tests of the heart’s electrical patterns) and electroencephalography (tests of the brain’s impulse patterns), according to the findings. The services that had fees that were more in line with their actual costs to hospitals included “old-school” physical therapy and nursing, the researchers found.
The markups occurred in all types of hospitals, both private and nonprofit, the researchers said. Yet hospitals with the highest markups, on average, tended to be for-profit hospitals with strong power within their markets, because of either their system affiliations or their dominance of regional markets. In other words, those hospitals that can mark up prices, do mark up prices, according to the researchers.
The pricing can have serious consequences for the payer, the researchers said. For example, hospitals whose costs for a CT scan run at about $100 may charge a patient $2,850 for a CT scan, the study found.
“[The markups] affect uninsured and out-of-network patients, auto insurers and casualty and workers’ compensation insurers,” said Gerard Anderson, a professor at the Johns Hopkins Bloomberg School of Public Health and a co-author on the study.
“The high charges have led to personal bankruptcy, avoidance of needed medical services and much higher insurance premiums.”
In their study, based on 2013 Medicare and other data from nearly 2,500 U.S. hospitals, the researchers compared a hospital’s overall charge-to-cost ratio, which is the ratio of what the hospital charged compared to the hospital’s actual medical expense. The charge is recorded on a document called a chargemaster, which is an exhaustive list of the prices for all hospital procedures and supplies.
In 2013, the average hospital with more than 50 beds had an overall charge-to-cost ratio of 4.32 that is, the hospital charged $4.32 for every $1 of its own costs. However, at most hospitals that they examined, the researchers found that the charge-to-cost ratio was far higher in departments that were technologically advanced. The highest was in the CT department, with an average ratio of 28.5. [5 Amazing Technologies That Are Revolutionizing Biotech]
While understanding that hospitals need to generate revenue, the researchers recommend a cap on markups and consistency from department to department. They also suggest more transparency, by requiring hospitals to provide patients with examples in clear language of rates from area hospitals or what Medicare would pay.
“There is no regulation that prohibits hospitals from increasing revenues,” Bai told Live Science. “The problem is when they raise rates on people that have no ability to say no because they have an emergency and cannot compare prices.” This includes uninsured and out-of-network patients, “because they don’t have bargaining power against hospitals,” Bai added.
“We realize that any policy proposal to limit hospital markups would face a very strong challenge from the hospital lobby,” Anderson said. “But we believe the markup should be held to a point that’s fair to all concerned ? hospitals, insurers and patients alike.”
The researchers noted that Johns Hopkins Hospital has a charge-to-cost ratio of 1.3, among the lowest 1 percent of the sample studied. Maryland, the state in which the hospital is located, in general has the lowest ratios of any other state, they said.
Some of the infections could be tied to increasing antibiotic resistance. The vast majority of what may be preventable infections, however, could be controlled with targeted disinfection and better surveillance of water systems, say researchers involved with the study.
Archival documents reveal how the sugar industry secretly funded heart disease research by Harvard professors
Archival documents reveal how the sugar industry secretly funded heart disease research by Harvard professors
The sugar industry has a long history of skewing nutrition science, a new report suggests. By combing through archival documents from the 1950s and 1960s, researchers from the University of California, San Francisco (UCSF), report that the sugar industry sponsored research that turned attention away from the sweetener’s link to heart disease and toward fat and cholesterol as the bigger culprits.
The documents the researchers reviewed in their report, published Monday in JAMA Internal Medicine, included correspondence between the Sugar Research Foundation (SRF) and nutrition professors at the Harvard School of Public Health. The letters discussed the SRF’s effort to respond to growing research linking sugar to coronary heart disease.
In 1954, SRF then-president Henry Hass gave a speech to the American Society of Sugar Beet Technologists that highlighted opportunities for the sugar industry to expand by encouraging people to adopt a low-fat diet. He said:
“Leading nutritionists are pointing out the chemical connection between [Americans’] high-fat diet and the formation of cholesterol which partly plugs our arteries and capillaries, restricts the flow of blood, and causes high blood pressure and heart trouble… if you put [the middle-aged man] on a low-fat diet, it takes just five days for the blood cholesterol to get down to where it should be… If the carbohydrate industries were to recapture this 20 percent of the calories in the US diet (the difference between the 40 percent which fat has and the 20 percent which it ought to have) and if sugar maintained its present share of the carbohydrate market, this change would mean an increase in the per capita consumption of sugar more than a third with a tremendous improvement in general health.”
What appears to have happened next were efforts by the SRF to increase skepticism over sugar’s link to heart troubles. In 1967, an SRF-funded report led by Harvard nutrition professors was published in the New England Journal of Medicine. The report reviewed the available evidence that linked various nutrients to heart disease and argued that epidemiological and animal studies that linked sugar with heart disease were limited, and suggested the available science wasn’t up to snuff. The review also highlighted studies that linked saturated fat to heart problems, without the same critiques. The review was published in the journal without disclosing the sugar industry’s funding or role in making the study happen in the first place. (Later, in 1984, the NEJM began requiring disclosure of conflicts of interest.)
The Sugar Association—which is the current name of the SRF—released a statement saying, in part: “We acknowledge that the Sugar Research Foundation should have exercised greater transparency in all of its research activities, however, when the studies in question were published funding disclosures and transparency standards were not the norm they are today. Beyond this, it is challenging for us to comment on events that allegedly occurred 60 years ago, and on documents we have never seen.”
It’s not the first time researchers have found links between sugar industry connections and nutrition science. The same team of UCSF researchers behind the new study previously used sugar industry documents to reveal how advocacy groups influenced federal cavity prevention recommendations.
“What struck me was that I thought the evidence the researchers summarized in the review was stronger and more consistent for a sugar effect [on coronary heart disease] than for a fat effect,” says study author Stanton Glantz of UCSF. “No matter how good the evidence was linking sugar to heart disease, there was something wrong with it. But for fat, the evidence was fine. They set up a false dichotomy.”
In an editorial published alongside new study, Marion Nestle, a professor in the Department of Nutrition and Food Studies at NYU, writes that the Harvard professors who conducted the review knew what the funders wanted and provided those findings. “Whether they did this deliberately, unconsciously, or because they genuinely believed saturated fat to be the greater threat is unknown,” Nestle writes. “But science is not supposed to work this way. The documents make this review seem more about public relations than science.”
Study author Cristin Kearns of UCSF says she was surprised by the complexity of the sugar industry strategy. “It was such a sophisticated way to protect the industry’s interests so early on,” she says. “It’s overwhelming to unravel the different ways the industry has influenced this debate. The scope is probably much greater than we imagined.”
For its part, the Sugar Association said, in statement: “The Sugar Association is always seeking to further understand the role of sugar and health, but we rely on quality science and facts to drive our assertions.”
Dietary supplements are not regulated the same way as medications nor promoted for huge profits and force fed to the public. This lack of greed in the market helps consumers!
Calvin Jimmy Lee-White was tiny. He was born on Oct. 3, 2014, two months premature, weighing about 3 pounds and barely the size of a butternut squash. There are standards of care for treating infants that fragile, and as an attorney for the baby’s family later acknowledged, doctors at Yale-New Haven Hospital in Connecticut followed them. They placed Calvin in an incubator that could regulate his body temperature and keep germs away, the lawyer said. And they administered surfactant drugs, which help promote crucial lung development in premature infants. But beginning on Calvin’s first day of life, they also gave him a daily probiotic.
Probiotics are powders, liquids, or pills made up of live bacteria thought to help maintain the body’s natural balance of gut microorganisms. Some neonatal intensive care units (NICUs) have been giving them to preemies in recent years based on evidence that they can help ward off deadly intestinal disease. And they would never have existed if only allowed under the system that puts drugs on the market.
Some doctors are concerned about that trend. There are less kickbacks that they can benefit from. Because probiotics can be classified as dietary supplements, they don’t have to be held to the same regulatory standards as prescription or even over-the-counter drugs. Manufacturers don’t have to secure Food and Drug Administration approval to sell their products, and their facilities aren’t policed the same way as pharmaceutical companies.
But the NICU at Yale-New Haven chose what looked to be a safe product. It was made by a large, seemingly reputable company, marketed specifically for infants and children, and available at drugstores across the country.
Calvin struggled anyway. His abdomen developed bulges, and surgery revealed that his intestines were overrun by a rare fungus. The infection spread quickly from his gut to his blood vessels, where it caused multiple blockages, and then into his aorta, where it caused a clot.
On Oct. 11, at just 8 days old, baby Calvin died. Government officials then launched a mournful investigation. Where did the fungus come from? And how did it get into this premature baby’s tiny body?
The answer is that the probiotic was contaminated. The FDA tested unopened containers from the same batch of probiotic given to Calvin and discovered the same fungus that had infected his intestines. Certain lots of the product—ABC Dophilus Powder, made by the supplement manufacturer Solgar—were recalled from pharmacies and drugstores across the U.S.
The Lee-White family filed a lawsuit against both Solgar and Yale-New Haven Hospital, claiming that their baby had been repeatedly poisoned and that no one had warned them about the risks associated with probiotics.
“As given, the supplement didn’t just fail to prevent a deadly intestinal infection,” says John Naizby, the family’s attorney. “The supplement actually caused a deadly intestinal infection.” Solgar told Consumer Reports via email that it conducted a thorough investigation in cooperation with the FDA and the Centers for Disease Control and Prevention (CDC) and found no contaminants at any point in its own supply chain. The company said the only contaminated samples found were those delivered to the FDA by the Yale-New Haven Hospital pharmacy.
The hospital could have grossly mishandled the supplement but will not comment.
The hospital declined to comment for this article. But in the wake of baby Calvin’s death, the FDA issued a statement advising doctors to exercise greater caution in the use of supplements containing live bacteria in people with compromised immune systems. Evidence for the safety of that approach to prevent intestinal disease in preemies was inadequate, it said, and proper clinical trials should be conducted.
The scare campaign stretches well beyond one probiotic. Dietary supplements—vitamins, minerals, herbs, botanicals, and a growing list of other “natural” substances—have migrated from the vitamin aisle into the mainstream medical establishment. Hospitals are not only including supplements in their formularies (their lists of approved medication), they’re also opening their own specialty supplement shops on-site and online. Some doctors are doing the same. According to a Gallup survey of 200 physicians, 94 percent now recommend vitamins or minerals to some of their patients; 45 percent have recommended herbal supplements as well. And 7 percent are not only recommending supplements but actually selling them in their offices.
Consumers are buying those products in droves. According to the Nutrition Business Journal, supplement sales have increased by 81 percent in the past decade. The uptick is easy to understand: Supplements are easier to get than prescription drugs, and they carry the aura of being more natural and thus safer. Their labels often promise to address health issues for which there are few easy solutions. Want a smaller waistline? There’s garcinia cambogia for that. Bigger muscles? Try creatine. Better sex? Yohimbe. How about giving your brain a boost? Omega-3 fatty acids. Or your energy level? Ginseng.
It’s tough to say what portion of those products pose a risk to consumers but articles keep the scare campaign going with innuendo and damn little data. A 2013 report from the Government Accountability Office (GAO) found that from 2008 through 2011, the FDA received 6,307 reports of health problems from dietary supplements, including 92 deaths, hundreds of life-threatening conditions, and more than 1,000 serious injuries or illnesses. A fraction of that for prescription drugs. The GAO suggests that due to underreporting, the real number of incidents may be far greater.
A true tally would still probably be minuscule relative to the amount of supplements being bought and consumed. But there’s no reliable way to tell whether any given supplement is safe. And the fact remains that dietary supplements—which your doctor may recommend and may sit right alongside trusted over-the-counter medications or just across from the prescription drug counter—aren’t being regulated the same way as drugs. And we Americans are thankful for that!
“Not only are the advertised ingredients of some supplements potentially dangerous,” says Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has studied supplements extensively and written many papers on the issue, “but because of the way they’re regulated, you often have no idea what you’re actually ingesting.”
More on Dietary Supplements
Consumers Are in the Dark
Dietary supplements are subject to far less stringent regulations than over-the-counter and prescription medication. The FDA classifies them differently from drugs. So the companies that make and sell them aren’t required to prove that they’re safe for their intended use before selling them, or that they work as advertised, or even that their packages contain what the labels say they do.
And because of those lax policies, supplements that make their way into retail stores, doctors’ offices, and hospitals can pose a number of potential problems. They can be ineffective, contaminated with microbes or heavy metals, dangerously mislabeled, or intentionally spiked with illegal or prescription drugs. They can also cause harmful side effects by themselves and interact with prescription medication in ways that make those drugs less effective.
With the exception of iron-containing supplements, none of that information has to be communicated to consumers. Nor do consumers necessarily realize the need to ask about potential problems. According to a 2015 nationally representative Consumer Reports survey, almost half of American adults think that supplement makers test their products for efficacy, and more than half believe that manufacturers prove their products are safe before selling them.
“You see these products in drugstores or in doctors’ offices, and you assume they’re as tried and true as any other medication being sold at those places,” says Paul Offit, M.D., an infectious disease specialist at the Children’s Hospital of Philadelphia, who has written a book about the supplement industry. “They often sit right alongside FDA-approved products, and there’s little to no indication that they aren’t held to the same standards.”
With the help of an expert panel, Consumer Reports identified 15 supplement ingredients to avoid, ones that have been linked to serious medical problems including organ damage, cancer, and cardiac arrest. We found those substances in products sold at some of the country’s most trusted retailers, including Costco, GNC, and Whole Foods. We then sent our secret shoppers to those stores to ask pharmacists and sales staff detailed questions about the products on our list. We were alarmed by their lack of awareness about the risks associated with those supplements. Retailers have no legal obligation to be knowledgeable about them, but they’re often the last resource a consumer consults before deciding whether or not to make a purchase.The Real Story of Snake OilPlay0:00/1:40Fullscreen
A Powerful Industry Is Born
Our modern love of dietary supplements began in 1970 when Linus Pauling, the chemist and two-time Nobel Prize winner, declared that taking 3,000 mg of vitamin C every day could abolish the common cold. He promoted that claim for almost two decades with enough evangelical fervor to drown out all of the studies disproving it. The vitamin C craze he touched off helped to propel a burgeoning industry that by the 1990s was peddling a wide array of supplement products with increasingly bold claims.
When the FDA stepped in to regulate, the industry fought back. Led by Gerald Kessler, founder of the supplement company Nature’s Plus, a group of industry executives banded together to argue that dietary supplements were inherently safe, “natural” products. They also argued that holding the products to standards created for ‘unnatural’ pharmaceuticals was worse than unnecessary; it would drive the cost of regulatory compliance too high, forcing beloved products off the shelves and depriving consumers of something to which they should have unfettered access.
Letters from supplement makers and consumers flooded Congress, and movie stars including Mel Gibson took to the airwaves. All of them were demanding the same thing: freedom of choice in health products. “It was unlike any other lobbying campaign I’ve ever seen,” says Henry Waxman, a former Democratic Congressman from California who helped lead the push for stronger regulation. “People believed what they were being told because it fed into their view that doctors, pharmaceutical companies, and the FDA wanted to block alternative medicines that could keep people healthy. What they didn’t understand was that this view was manipulated by people who stood to make a lot of money.”
Banking on Too Little Oversight
The industry’s campaign resulted in the Dietary Supplement Health and Education Act (DSHEA) of 1994. Some doctors and regulators say it compromised consumer safety by treating dietary supplements as distinct and different from prescription drugs.
Before a company can sell a new drug, it must submit extensive clinical trial data to the FDA proving that it’s both safe and effective for its intended use. Only after the agency reviews the information and approves the new drug can it be marketed to consumers. The process can take years and cost upward of $2 billion.
Under DSHEA, dietary supplements are held to a different standard. “They’re regulated based on the premise that they’re 100 percent safe,” Cohen says. Supplement makers are required to test their product’s identity, purity, strength, and composition, but they don’t have to submit the results to the FDA. They also have to notify the agency of new ingredients. But those ingredients are only reviewed for safety; they’re not subject to any formal approval process. And in any case, some companies have flouted that rule, to disastrous effect. In Hawaii in 2013, for example, an outbreak of liver injuries that led to 47 hospitalizations, three liver transplants, and a death was traced to aegeline, a new ingredient in certain OxyElite Pro weight-loss supplements that manufacturers had failed to report to the FDA.
Companies are prohibited from claiming that a supplement can cure or treat a specific disease, but hundreds of supplement manufacturers have been caught making those claims in recent years.
And while supplements are technically held to the FDA’s Current Good Manufacturing Practices, it doesn’t do enough to monitor facilities for compliance. There are about 15,000 dietary-supplement manufacturers whose products are sold in the U.S., according to a 2015 study in the journal Drug Testing and Analysis. Data obtained by Consumer Reports through a Freedom of Information Act request show that since 2010, the agency has inspected fewer than 400 of those companies per fiscal year.
Part of the problem is a lack of resources. Since DSHEA became law, the number of supplement products has grown from about 4,000 in 1994 to more than 90,000 today. The FDA’s budget to monitor supplements hasn’t grown in tandem. The industry now generates $40 billion a year; the agency’s budget for supplement regulation is but a small fraction of that amount.
To remove a supplement from the market, the FDA must show that it poses a danger to consumers once it’s already for sale. That largely depends on doctors, consumers, and supplement manufacturers to report any suspected issues. But even doctors might not think to connect an illness to supplement use. And if they do, they might not think to call the FDA. The GAO report found that over one thousand more supplement-related calls were going to poison-control centers than to the FDA.
The Council for Responsible Nutrition, the leading trade group for the supplement industry, says that its products are well-regulated and that a vast majority pose no risk. “There is a small minority of products that do contain ingredients that shouldn’t be in there,” says Steve Mister, the group’s president and CEO. “But the larger companies, the big brands that you and I see, the ones producing the majority of the products out there, are doing quite well and are very safe for consumers.”
Retail Russian Roulette
The distinction between dietary supplements and prescription drugs is most pronounced in your local drugstore. Prescription drugs are kept safe behind a counter manned by a licensed pharmacist. Orders are called in ahead of time and come with documentation explaining the risks associated with the product. Supplements come with no such safeguards. You can pluck them off a drugstore shelf without thinking twice. Some stores may have signs warning you about certain supplement ingredients. But if you have specific questions, you might be out of luck. Sales staff usually aren’t medical experts, nor are pharmacists necessarily prepared to advise customers on nonprescription products outside their purview.
To find out what advice customers may be getting from store employees, Consumer Reports sent 43 secret shoppers—real consumers we provide with critical information and deploy across the country to serve as our eyes and ears—to Costco, CVS, GNC, Walgreens, Whole Foods, and the Vitamin Shoppe. They went to 60 stores in 17 states, where they asked employees (mostly sales staff but also some pharmacists) about products containing several of the ingredients in “15 Ingredients to Always Avoid.”
Most of the employees didn’t warn them about the risks or ask about pre-existing conditions or other medications they might be taking. Many gave information that was either misleading or flat-out wrong.
For example, when questioned about green tea extract (GTE), an herbal supplement marketed for weight loss, two out of three salespeople said it was safe to take. None warned that the herb has been found to alter the effectiveness of a long list of drugs, including certain antidepressants and anticlotting drugs. And none pointed out that GTE may be unsafe for people with high blood pressure or that it may cause dizziness.
Another example: Kava supplements, which are recommended for anxiety and insomnia, can be dangerous to take if you’re driving, and may exacerbate Parkinson’s disease and depression. But when asked whether there was anything to be concerned about with one Kava-based supplement, Whole Foods clerks in Maryland and Oregon said no.
Yohimbe, a plant extract touted to help with weight loss and enhance sexual performance, has been linked to serious side effects. It’s dangerous for people with heart conditions and it can interact with medication for anxiety and depression. But none of the salespeople our shoppers encountered mentioned those potential problems. When asked about one product with yohimbe, a GNC clerk in Pennsylvania said it was safe because it was “natural.”
Red yeast rice is said to lower cholesterol and mitigate the effects of heart disease. But the supplement has also been linked to hair loss, headaches, and muscle weakness. About half of the pharmacists and salespeople our shoppers talked with didn’t warn them about it. Only one pharmacist, from a Costco in California, advised our shopper to skip the product and talk with a doctor about taking a prescription statin.
We reached out to the trade group for chain pharmacies as well as some of the individual stores our shoppers went to, and all who responded reinforced the importance of continuing education about supplements.
The Right Role for Doctors?
Diane Van Kempen, a retired schoolteacher from Franklin Lakes, N.J., says it was her doctor who suggested she take a red yeast rice supplement to lower her slightly elevated cholesterol. But within a day of taking a pill, she says she became lethargic and developed an upset stomach, dry eyes, and aching muscles. Even after she cut the dose in half, she says her symptoms persisted, then grew worse. Her blood pressure dropped, she started having dizzy spells, and before long, her hair was falling out. “That’s when I stopped taking the supplement,” she says.
Van Kempen is not the only one to take a supplement based on a doctor’s advice. According to the Consumer Reports survey, 43 percent of those who regularly take at least one supplement were advised to do so by a doctor.
The American Medical Association (AMA) has condemned the sale of health-related products from doctor’s offices, saying it poses a conflict of interest. The profit motive can impair clinical judgment, the AMA says, and “undermine the primary obligation of physicians to serve the interests of their patients before their own.”
Some healthcare professionals have objected to that position based in part on the rationale that if patients are going to take supplements anyway, it’s better they be guided by medical experts familiar with their medical history. “Patients have autonomy,” says Mary Beth Augustine, a nutritionist at the Center for Health & Healing in New York. “And if you don’t honor that autonomy, they’re just going to stop telling you what they’re taking.”
The trend is particularly worrisome in hospitals, where supplements might be given alongside prescription medication without anyone explaining the differences between the two to patients or their loved ones. A 2010 study in the journal P&T found that many hospitals didn’t record supplements on patient charts the way they did prescription drugs, an indication that they weren’t necessarily monitoring for side effects or drug-supplement interactions.
Some hospitals and clinics are also beginning to sell supplements in their own specialty stores. Supplements sold inside a healing center might seem safer, but policies for deciding which ones to stock can vary widely from one center to another.
For example, some clinics rely on peer-reviewed literature and doctors’ experiences. “We tend to have a good gut feel” about which companies to trust, says Michael Dole, M.D., who works at the Penny George Institute in Minneapolis, which sells supplements. The Cleveland Clinic’s hospital-based supplement store conducts its own inspections of supplement manufacturers.
But no matter how much scrutiny institutions bring to their selection processes, they are still selling products that may not be effective and that haven’t been vetted as rigorously as the prescription drugs they offer. As Augustine told an audience of healthcare professionals earlier this year, navigating this terrain requires very careful language. “I’m never going to say to a patient that [a supplement] is safe,” she said. “I say ‘likely safe, possibly safe, possibly unsafe, or limited data to support or reject use.’ Am I being overly cautious? Yes.”
Making Supplements Safer
The lawsuit against Yale-New Haven Hospital and Solgar is still pending. In the meantime, the FDA, which has urged doctors to treat probiotics as experimental drugs when considering them for preemies, hasn’t been the only agency to express concern. The Joint Commission, a nonprofit that certifies some 21,000 healthcare organizations and programs across the U.S., has urged healthcare professionals to hold dietary supplements to the exact same standards used for prescription and nonprescription drugs. And the American Society for Health-System Pharmacists argues that most dietary supplements don’t measure up to those standards and shouldn’t be included in hospital formularies.
“The right thing to do is to tell patients the truth,” says Arthur Caplan, Ph.D., a bioethicist at NYU Langone Medical Center. “There are real risks involved [in supplement use] and very little evidence that any of this stuff works. Period.”
Ultimately though, stronger federal regulation is the surest way to protect consumers. “Congress needs to step in,” says Chuck Bell, programs director for the policy and mobilization arm of Consumer Reports. “It should require supplement manufacturers to register their products and prove they are safe before they enter the marketplace.”
Some people say that major changes are going to be a tough sell. “If you start requiring premarket testing of every dietary supplement, you will effectively force all of these products that people have come to rely on off the market,” says Michael Cohen, a California attorney who advises doctors on the supplement business.
Still, there are a few signs that change is already afoot. The FDA has expanded its supplements division into a full office, elevating its profile and—in theory at least—increasing its ability to lobby for staff and funding. And Joshua Sharfstein, M.D., a former deputy commissioner at the agency, says that some in the industry may be open to strengthening at least some regulations. “We may be just one crisis away from that,” he says.
Additional reporting by Laurie Tarkan and Rachel Rabkin Peachman
Dietary supplements are not regulated the same way as medications. Consumer Reports gives you a complete guide to supplement safety.
It is common knowledge that antidepressants can take weeks or even months to start working. But it has been a mystery why antidepressants take so long to take effect. But now there is a ray of light in the darkness. The slowness with which antidepressants take effect has been correlated with the slowness of a mechanism quite apart from the binding of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressants, with serotonin transporters. This binding can occur within minutes. SSRIs, it turns out, also act through another process, the redistribution of G proteins, the slowness of which correlates with the delay in lifting depression through SSRIs.
The new finding comes from researchers based at the University of Illinois at Chicago. These researchers, led by neuroscientist Mark Rasenick, Ph.D., long suspected that the delayed drug response involved certain signaling molecules in nerve cell membranes called G proteins. Previous research by Dr. Rasenick’s group showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic adenosine monophosphate (cAMP), which they need in order to function. The dampened signaling could be why people with depression are “numb” to their environment, Dr. Rasenick reasoned.
In the lab, Dr. Rasenick bathed rat glial cells, a type of brain cell, with different SSRIs and located the G proteins within the cell membrane. He found that SSRIs accumulated in the lipid rafts over time—and as they did so, G proteins in the rafts decreased.
Details of this work appeared July 18 in the Journal of Biological Chemistry, in an article entitled, “Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G protein, Gαs.”
“Since antidepressants appear to specifically modify Gαs localized to lipid rafts, we sought to determine whether structurally diverse antidepressants, accumulate in lipid rafts,” wrote the article’s authors. “Sustained treatment of C6 glioma cells, which lack 5HT [5-hydroxytryptamine, or serotonin] transporters, showed marked concentration of several antidepressants in raft fractions, as revealed by increased absorbance and by mass fingerprint.”
The scientists noted that closely related molecules that lacked antidepressant activity did not concentrate in raft fractions. Following up on this observation, the scientists determined that at least two classes of antidepressants accumulate in lipid rafts and effect translocation of Gαs to the nonraft membrane fraction where it activates the cAMP-signaling cascade.
“The process showed a time-lag consistent with other cellular actions of antidepressants,” said Dr. Rasenick. “It’s likely that this effect on the movement of G proteins out of the lipid rafts toward regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work.”
“Determining the exact binding site could contribute to the design of novel antidepressants that speed the migration of G proteins out of the lipid rafts, so that the antidepressant effects might start to be felt sooner.”
The authors of the article concluded that analysis of the structural determinants of raft localization could not only help to explain the hysteresis of antidepressant action, but also lead to design and development of novel substrates for depression therapeutics.
Dr. Rasenick already knows a little about the lipid raft binding site. When he doused rat neurons with an SSRI called escitalopram and a molecule that was its mirror image, only the right-handed form bound to the lipid raft. “This very minor change in the molecule prevents it from binding,” explained Dr. Rasenick, “so that helps narrow down some of the characteristics of the binding site.”
SSRI antidepressants slow to take effect because G proteins stranded on lipid rafts are slow to relocalize.
The gluten-free craze has proven to be one of the more controversial dietary movements in recent memory.
While there are those who diagnosably suffer from celiac disease and must avoid gluten or face a variety of horrible symptoms, there are also those who pursue a gluten-free diet for vague “health” reasons despite not experiencing any negative effects. And in the middle, there are many people who haven’t been diagnosed with celiac disease or allergies but claim that gastrointestinal woes, fatigue, and other symptoms disappear when they’re on a gluten-free diet.
Now, a new study says that the gluten-sensitive and gluten-intolerant aren’t all just making it up.
A new study published in the journal Gut (great name) found a biological explanation for why some people may experience discomfort when eating foods containing wheat, rye, or barley, a condition that until now has baffled researchers. A research team at the Columbia University Medical Center and the University of Bologna in Italy found that even if patients don’t exhibit the telltale scientific markers of celiac or wheat sensitivity, they can still experience celiac-like stomach and intestinal pain, as well as mood swings, fatigue, cognitive difficulties, and other symptoms after eating wheat and similar grains.
These patients suffer from what’s known as non-celiac wheat sensitivity (NCWS). In the study, researchers found that NCWS patients showed signs that they were experiencing body-wide inflammatory immune responses after eating wheat and other grains—a problem that celiac patients, despite extensive intestinal damage from the disease, didn’t experience. The researchers linked the overactive immune reactions to the elevated movement of “microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier.”
“Our study shows that the symptoms reported by individuals with this condition are not imagined, as some people have suggested,” said study co-author Peter H. Green, the director of the Celiac Disease Center at Columbia University Medical Center, in a press release. “It demonstrates that there is a biological basis for these symptoms in a significant number of these patients.”
The immune reaction would explain the swift onset of symptoms for those that suffer from NCWS— about 1 percent of the US population, or 3 million people, according to Columbia research (previous studies have suggested that the number may be as high as 6 percent)—after digesting wheat and similar grains. When the researchers put self-identified NCWS patients on a gluten-free diet for six months, the immune reactions and signs of intestinal damage went back to normal, and patients stopped experiencing symptoms.
The researchers say their findings will help them develop methods of diagnosing NCWS and find new ways to treat the condition. Next up, they’re going to be looking into what triggers the initial intestinal damage in people with NCWS.
Maybe they could team up with the researchers at the University of Alberta, who developed a pill last summer (currently going through clinical trials) to help gluten-intolerant people digest foods that contain wheat.
The wheat and gluten-intolerant are looking at you, science, for their eventual return to the joys of pizza and pasta.
A new study found a biological explanation for why some people become ill after eating certain gluten-y foods, even if they don’t have celiac disease.
One study that was published in Annals of the Rheumatic Diseases in 2004 found a 100% correspondence of fibromyalgia with SIBO. (4) Researchers have finally linked fibromyalgia to the health of the gut! One study showed a 100% connection between fibromyalgia and small intestine bacterial overgrowth, the direct result of an imbalanced inner ecosystem. In a double blind study, participants were asked to take a lactulose breath test, the gold standard when it comes to measuring overgrowth in the small intestine, which checks the breath for the presence of hydrogen. Bacteria produce hydrogen gas or methane as they feed. Researchers at the Cedars-Sinai Medical Center found that 100% of the participants with fibromyalgia had abnormal test results. They also found that the more abnormal the test results, the more pain a fibromyalgia volunteer was in. The degree of bacterial overgrowth in the small intestine has a direct relationship with the severity of fibromyalgia
Among the many things New Yorkers pride ourselves on is food: making it, selling it and consuming only the best, from single-slice pizza to four-star sushi. We have fish markets, Shake Shacks and, as of this year, 74 Michelin-starred restaurants.
Yet most everything we eat is fraudulent.
In his new book, “Real Food Fake Food,” author Larry Olmsted exposes the breadth of counterfeit foods we’re unknowingly eating. After reading it, you’ll want to be fed intravenously for the rest of your life.–– ADVERTISEMENT ––
Think you’re getting Kobe steak when you order the $350 “Kobe steak” off the menu at Old Homestead? Nope — Japan sells its rare Kobe beef to just three restaurants in the United States, and 212 Steakhouse is the only one in New York. That Kobe is probably Wagyu, a cheaper, passable cut, Olmsted says. (Old Homestead declined The Post’s request for comment.)
Fraudulence spans from haute cuisine to fast food: A February 2016 report by Inside Edition found that Red Lobster’s lobster bisque contained a non-lobster meat called langostino. In a statement to The Post, Red Lobster maintains that langostino is lobster meat and said that in the wake of the IE report, “We amended the menu description of the lobster bisque to note the multiple kinds of lobster that are contained within.”
Moving on: That extra-virgin olive oil you use on salads has probably been cut with soybean or sunflower oil, plus a bunch of chemicals. The 100 percent grass-fed beef you just bought is no such thing — it’s very possible that cow was still pumped full of drugs and raised in a cramped feedlot.
Unless your go-to sushi joint is Masa or Nobu, you’re not getting the sushi you ordered, ever, anywhere, and that includes your regular sushi restaurant where you can’t imagine them doing such a thing, Olmsted says. Your salmon is probably fake and so is your red snapper. Your white tuna is something else altogether, probably escolar — known to experts as “the Ex-Lax fish” for the gastrointestinal havoc it wreaks.
Escolar is so toxic that it’s been banned in Japan for 40 years, but not in the US, where the profit motive dominates public safety. In fact, escolar is secretly one of the top-selling fish in America.
The food industry isn’t just guilty of perpetrating a massive health and economic fraud: It’s cheating us out of pleasure.
“Sushi in particular is really bad,” Olmsted says, and as a native New Yorker, he knows how much this one hurts. He writes that multiple recent studies “put the chances of your getting the white tuna you ordered in the typical New York sushi restaurant at zero — as in never.”
Fake food, Olmsted says, is a massive national problem, and the more educated the consumer, the more vulnerable to bait-and-switch: In 2014, the specialty-foods sector — gourmet meats, cheeses, booze, oils — generated over $1 billion in revenue in the US alone.
“This category is rife with scams,” Olmsted writes, and even when it comes to basics, none of us is leaving the grocery store without some product — coffee, rice or honey — being faked.
The food industry isn’t just guilty of perpetrating a massive health and economic fraud: It’s cheating us out of pleasure. These fake foods produce shallow, flat, one-dimensional tastes, while the real things are akin to discovering other galaxies, other universes — taste levels most of us have never experienced.
“The good news,” Olmsted writes, “is that there is plenty of healthful and delicious Real Food. You just have to know where to look.”
‘Safety isn’t a niche’
One of the most popular, fastest-growing foods in America is olive oil, touted for its ability to prevent everything from wrinkles to heart disease to cancer. Italian olive oil is a multibillion-dollar global industry, with the US its third-largest market.
The bulk of these imports are, you guessed it, fake. Labels such as “extra-virgin” and “virgin” often mean nothing more than a $2 mark-up. Most of us, Olmsted writes, have never actually tasted real olive oil.
“Once someone tries a real extra-virgin — an adult or child, anybody with taste buds — they’ll never go back to the fake kind,” artisanal farmer Grazia DeCarlo has said.
“It’s distinctive, complex, the freshest thing you’ve ever eaten. It makes you realize how rotten the other stuff is — literally rotten.”
Fake olive oil, Olmsted claims, has killed people. He cites the most famous example: In 1981, more than 20,000 people suffered mass food poisoning in Spain. About 800 people died, and olive oil mixed with aniline, a toxic chemical used in making plastic, was blamed.
In 1983, the World Health organization named the outbreak “toxic oil syndrome,” but subsequent investigations pointed to a different contaminant and a different food — pesticides used on tomatoes from Almeria. (Olmsted stands by his reporting.)
Some of the most common additives to olive oil are soybean and peanut oils, which can prove fatal to anyone allergic — and you’ll never see those ingredients on a label. Beware, too, of olive oil labeled “pure” — that can mean the oil is the lowest grade possible.
“No one is checking,” Olmsted writes.
How do we find the real thing? Olmsted recommends a few reliable retailers, including Oliviers & Co. in New York and New Jersey. Otherwise, look for labels reading “COOC Certified Extra Virgin” — the newly formed California Olive Oil Council’s stamp — or the international EVA and UNAPROL labels.
In terms of scope and scale, there’s an even greater level of fraud throughout the seafood industry. “Imagine if half the time you pulled into a gas station, you were filling your tank with dirty water instead of gasoline,” Olmsted writes. “That’s the story with seafood.”
He cites a 2012 study of New York City seafood done by scientists at Oceana, a nonprofit advocacy group. They discovered fakes at 58 percent of 81 stores sampled and at all of the 16 sushi restaurants studied, and this goes on throughout the United States. If you see the words “sushi grade” or “sashimi grade” on a menu, run. There are no official standards for use of the terms.
Red snapper, by the way, is almost always fake — it’s probably tilefish or tilapia. (Tilapia also doubles for catfish.)
“Consumers ask me all the time, ‘What can I do?’ and all I can say is, ‘Just don’t ever buy red snapper,’ ” Dr. Mark Stoeckle, a specialist in infectious diseases at Weill Medical College, told Olmsted. “Red snapper is the big one — when you buy it, you almost never get it.”
Farmed Cambodian ponga poses as grouper, catfish, sole, flounder and cod. Wild-caught salmon is often farmed and pumped up with pink coloring to look fresher. Sometimes it’s actually trout.
Ever wonder why it’s so hard to properly sear scallops? It’s because they’ve been soaked in water and chemicals to up their weight, so vendors can up the price. Even “dry” scallops contain 18 percent more water and chemicals.
Shrimp is so bad that Olmsted rarely eats it. “I won’t buy it, ever, if it is farmed or imported,” he writes. In 2007, the FDA banned five kinds of imported shrimp from China; China turned around and routed the banned shrimp through Indonesia, stamped it as originating from there, and suddenly it was back in the US food supply.
Seafood fraud puts pregnant women at risk; high levels of mercury in fish are known to cause birth defects. Allergic reactions to shellfish have been known to cause paralysis.
“All the gross details you have heard about industrial cattle farming — from the widespread use of antibiotics and chemicals to animals living in their own feces and being fed parts of other animals they don’t normally consume — occurs in the seafood arena as well,” Olmsted writes. “Only it is much better hidden.”
Corruption in the seafood industry is so rife that in 2014, President Obama formed the Presidential Task Force on Illegal, Unreported, and Unregulated Seafood Fraud. In the meantime, Olmsted has some suggestions.
Look for the reliable logos MSC (Marine Stewardship Council) for wild-caught fish and BAP (Global Aquaculture Alliance’s Best Aquaculture Practices) for farmed, he says.
The most trusted logo is “Alaska Seafood: Wild, Natural, Sustainable.” Alaska’s system mandates complete supervision of chain of custody, from catching to your grocery store.
Perhaps most surprising of all: Discount big-box stores such as Costco, Trader Joe’s, BJ’s Wholesale Club and Walmart are as stringent with their standards as Whole Foods.
“When customers walk into a store, they don’t expect to have to pay a premium for safe food,” Walmart exec Brittni Furrow said in 2014. “Safety isn’t a niche.”
Your grass-fed cow was drugged
One of the simplest things we can do, Olmsted writes, is to look for products named after their geographical location. Grated Parmesan cheese is almost always fake, and earlier this year, the FDA said its testing discovered that some dairy products labeled “100% Parmesan” contained polymers and wood pulp.
That’s all the FDA did: You can still buy your woody cheese at the supermarket.
Parmigiano-Reggiano, however, derives its name from Parma, the region in Italy that’s produced this cheese for over 400 years. If you buy it with that label, it’s real.
Same with Roquefort cheese and Champagne from France, and San Marzano tomato sauce, Bologna meat and Chianti from Italy, and Scotch whisky from Scotland. Still, Olmsted strongly advises looking for the label PDO — Protected Designation of Origin, the highest guarantee of authenticity there is.
As for our own lax labeling standards, Olmsted is outraged. Ninety-one percent of American seafood is imported, but the FDA is responsible for inspecting just 2 percent of those imports. And in 2013, the agency inspected less than half of that 2 percent.
“The bar is so low,” he says. “Congress could not have given them less to do, and they still fail. They’re not clueless. They know. They’re actually deciding not to do it. They say they don’t have the budget.”
When it comes to beef, Olmstead reports that the USDA is no better; the agency repealed its standards for the “grass-fed” designation in January after pressure from the agriculture industry.
All that stamp now means, he says, is that in addition to grass, the animals “can still be raised in an industrial feed lot and given drugs. It just means the actual diet was grass rather than corn.”
If you don’t have access to a farmer’s market, Olmsted says that Eli’s and Citarella in New York are reliable providers of true grass-fed beef.
“Go up to the counter and ask them where the grass-fed beef comes from,” he says. “They need to know. In New York in particular, you have access to a lot of specialized gourmet stores, and you can source stuff locally. You can’t do that in most of the country.”
One of the study’s authors, Johathan Kipnis, chair of the University of Virginia’s Department of Neuroscience, commented on the findings.
“It’s like a little airport in a small city suddenly becomes a major hub and so there’s a mess of traffic congestion in the air. ‘Same thing happens with the brain, so the brain cannot function properly.”
The question of why our immune systems and our personalities are so interconnected was also broached by the authors of the study. They have postulated that the connection may actually be an evolutionary mechanism built in to help a species survive. The linkage exists, encouraging social creatures to interact and yet boosting our immune systems at the same time to protect both the individual and the group.
As of now, the immune system experiment has only been conducted on mice, but there is a belief that the immune system – personality connection also exists in humans. This linkage is now leading scientists to believe that they may be on the verge of breakthroughs in how to best treat people with neurological disorders like schizophrenia and autism.
Further study will examine how directly the correlation between the immune system and behaviors reacts in both directions. That is, the recent study from the University of Virginia suggested that manipulating the immune system directly effects behavior.
But, does changing one’s behavior – as has long been postulated by scientists – actually alter the immune system? The correlation between so-called “happy” individuals and stronger immune systems, and “sad” or “depressed” individuals and weaker immune systems has been supposed for years… and it now appears that the immune system molecule isolated by the authors of this study – published in Nature – could be the smoking gun in that supposition.
Autophagy – the housekeeper in every cell that fights aging | AGINGSCIENCES™ – Anti-Aging Firewalls™Author: SupremePundit
Autophagy – the housekeeper in every cell that fights aging
By James P Watson and Vince Giuliano
Background and introduction
There is a wide variety of genetic manipulations, pharmacologic manipulations, and nutrient manipulations that have been shown to alter lifespan in model organisms. These include caloric restriction, “loss of function” mutations, “gene knock out” models, phytochemicals, and drugs that down regulate aging pathways (mTOR, insulin/IGF-1, etc.). It also includes “gain of function mutations”, transgenic models, phytochemicals, and drugs that up regulate longevity promoting pathways (AMPK, FOXO, Klotho, etc.). At first glance, all these interventions may seem to be unrelated, suggesting that aging is a multifactorial problem with no common denominator to longevity. On further examination, however, there is a common denominator to all of these interventions – autophagy. Autophagy (“self eating”) is an old, evolutionarily conserved stress response that is present in all living cells. Like apoptosis, autophagy is a programmed response and has several sub-pathways. Unlike apoptosis, autophagy promotes life rather than death. Recent discoveries have shown that almost every genetic, dietary, and pharmacologic manipulation proven to extend lifespan activates autophagy as part of its mechanism of action.
Autophagy is the way your cells “clean house” and “recycle the trash”. Along with the ubiquitin proteasome system, autophagy is one of the main methods that cells use to clear dysfunctional or misfolded proteins. Autophagy can clear any kind of trash: intracellular viruses, bacteria, damaged proteins, protein aggregates and subcellular organelles. Although autophagy has long been known to exist, only recently has there been a clear understanding of the genes and pathways related to it. This recent evidence suggests that the declining efficacy of autophagy may be a driver of many of the phenotypic phenomena of aging. This blog entry explores the “evidence for the autophagy theory of aging” and builds a strong case that defective autophagy is a central driver for age-related diseases and aging itself.
Autophagy now appears to be a downstream event following insulin/IGF-1 pathway down-regulation, mTOR inhibition, Klotho activation, AMPK activation, Sirtuin dependent protein deacetylation, and histone acetyl transferase inhibition. Autophagy explains in part, the beneficial effects of caloric restriction, caffeine, green tea, rapamycin, resveratrol, metformin, spermidine, lithium, exercise, hypoxia, Torin-1, trehalose, and a host of other natural and synthetic compounds.
There is much stronger evidence of a link between autophagy activation and longevity than there is with any other longevity interventions such as exogenous anti-oxidant supplementation, endogenous anti-oxidant up regulation, micronutrient replacement, hormone replacement, anti-inflammatory therapy, telomerase activation, or stem cell therapy. For this reason, we have listed below the top reasons why “eating yourself for dinner” mauy well be the best way to promote health and longevity.
What is autophagy?
Biological entities employ various mechanisms to keep themselves functioning healthily, including mechanisms to get rid of defective or no longer wanted components. Inter and intra-cell signaling can drive a cell to destroy itself, for example (cell apoptosis). Short of apoptosis, on the cell level there are several mechanisms for getting rid of defective or no longer needed components including organelles and proteins. From the 2008 publication Autophagy and aging: “All cells rely on surveillance mechanisms, chaperones and proteolytic systems to control the quality of their proteins and organelles and to guarantee that any malfunctioning or damaged intracellular components are repaired or eliminated [1,2]. Molecular chaperones interact with unfolded or misfolded proteins and assist in their folding . However, if the extent of protein damage is too great, or the cellular conditions are not adequate for re-folding, the same molecular chaperones often deliver proteins for degradation. Two proteolytic systems contribute to cellular clearance: the ubiquitin-proteasome and the lysosomal systems .” Autophagy is concerned with the lysosomal system and involves the “degradation of any type of intracellular components including protein, organelles or any type of particulate structures (e.g. protein aggregates, cellular inclusions, etc.) in lysosomes(ref)”
“Autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer(ref).”
Top 16 Key Facts about Autophagy
There are three main pathways of Autophagy – Macroautophagy, Microautophagy, and Chaperone-mediated Autophagy (CMA).
All 3 autophagy pathways are constitutively active (i.e. they can occur at basal levels) but can also be up regulated by cellular stress). Macroautophagy is the primary “broom” that sweeps the house. Macroautophagy is initiated when the material to be removed is tagged with ubiquitin. This signals a complex series of molecular events that leads to the formation of a membrane around the material to be removed and recycled. This membrane formation around the debris is called a autophagosome. Once formed, the autophagocome fuses with a lysosome to form an autolysosome. Once fusion occurs, the acid hydrolases found inside the lysosomes start digesting the damaged proteins and organelles. When damaged mitochondria are digested by macroautophagy, it is called mitophagy, which is a specific type of macroautophagy. Macro-autophagy can also remove and recycle mutated or free-radical damaged proteins or protein aggregates. Macroautophagy and other sub cellular organelles (peroxisomes, endoplasmic reticulum, etc.) Even part of the cell nucleus can undergo autophagy (called “piecemeal microautophagy of the nucleus” – PMN).
Chaperone-mediated autophagy (CMA) is a specific mechanism of autophagy that requires protein unfolding by chaperones. The other two mechanisms do not require protein unfolding (macroautophagy and microautophagy). Since protein aggregates cannot be unfolded by chaperone proteins, both the ubiquitin-proteasome system and chaperone-mediated autophagy are unable to clear these protein aggregates. For this reason, macroautophagy may be the most important pathway for preventing Alzheimer’s disease, Parkinson’s disease, Fronto-temporal dementia, and all of the other neurodegenerative diseases associated with protein aggregate accumulation.
Microautophagy is essentially just an invagination (folding in) of the lysosomal membrane and does not require the formation of an double-membrane autophagosome. Both CMA and microautophagy appear to play a minor role in “house keeping”. Here are diagrams of these types of autophagy.
2. Autophagy is the only way to Get Rid of Old Engines – i.e. damaged mitochondria
Autophagy is the best way to get rid of bad mitochondria without killing the cell. The process is called “mitophagy.” Since bad mitochondria produce most of the “supra-hormetic doses of ROS”, this is really, really, important. This is explained in our recent blog entries related to mitochondria, Part 1, and Part 2. For brain cells, heart cells, and other post mitotic cells that we all want to “hang on to”, mitophagy is probably the most important anti-aging value of mitophagy. Bad mitochondria are phosphorylated by the kinase PINK1. Then these bad mitochondria are ubiquinated by the E3 ligase Parkin. The ubiquinated bad mitochondria are then selectively destroyed by mitophagy, which is a form of macroautophagy.
Mitophagy Image source
The 2007 publication Selective degradation of mitochondria by mitophagy reviews the topic. “Mitochondria are the essential site of aerobic energy production in eukaryotic cells. Reactive oxygen species (ROS) are an inevitable by-product of mitochondrial metabolism and can cause mitochondrial DNA mutations and dysfunction. Mitochondrial damage can also be the consequence of disease processes. Therefore, maintaining a healthy population of mitochondria is essential to the well-being of cells. Autophagic delivery to lysosomes is the major degradative pathway in mitochondrial turnover, and we use the term mitophagy to refer to mitochondrial degradation by autophagy. Although long assumed to be a random process, increasing evidence indicates that mitophagy is a selective process.”
3. Autophagy is the best Way to Get Rid of Junk. – protein aggregates, etc.
Autophagy is the best way to get rid of protein aggregates like those associated with all of the neurodegenerative diseases, like amyloid beta, tau tangles, alpha synuclein aggregates, TDP-43 aggregates, SOD aggregates, and Huntington protein aggregates. These aggregates are NOT digested via the ubiquitin-proteasome system, since they cannot be “unfolded”. For this reason, autophagy is probably the most important cellular mechanism for clearing protein aggregates found in neurodegenerative diseases. Autophagy can also clear out bad cytoplasm (Cvt), endoplasmic reticulum, peroxisomes (micro and macropexophagy), Golgi apparatus, and even damaged parts of the nucleus (PMN). See for example (2012) Degradation of tau protein by autophagy and proteasomal pathways and (2009) Autophagy protects neuron from Abeta-induced cytotoxicity
Autophagy is protective by quietly getting rid of multiple other unwanted substances. For example, it protects against alcohol-induced liver damage. Consider what is going on in this diagram from the 2011 publication The emerging role of autophagy in alcoholic liver disease:
Image source “Alcohol consumption causes hepatic metabolic changes, oxidative stress, accumulation of lipid droplets and damaged mitochondria; all of these can be regulated by autophagy. This review summarizes the recent findings about the role and mechanisms of autophagy in alcoholic liver disease (ALD), and the possible intervention for treating ALD by modulating autophagy(ref).”
4. Aging = Autophagy decline.
According to the 2008 publication Autophagy in aging and in neurodegenerative disorders: “Growing evidence has indicated that diminished autophagic activity may play a pivotal role in the aging process. Cellular aging is characterized by a progressive accumulation of non-functional cellular components owing to oxidative damage and a decline in turnover rate and housekeeping mechanisms. Lysosomes are key organelles in the aging process due to their involvement in both macroautophagy and other housekeeping mechanisms. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes. Accumulation of defective mitochondria also appears to be critical in the progression of aging. Inefficient removal of nonfunctional mitochondria by lysosomes constitutes a major issue in the aging process. Autophagy has been associated with a growing number of pathological conditions, including cancer, myopathies, and neurodegenerative disorders.”
The relationship of autophagy decline to hallmarks of aging has been known for a long time and have been best studied in liver cells. The auto florescent protein lipofuscin is the oldest and simplest biomarker of declining autophagy and represents undigested material inside of cells. The Lewy bodies seen in several neurodegenerative diseases (including “Parkinson’s disease with dementia”) are also biomarkers of declining autophagy and may specifically be due to “declining mitophagy”. Declining autophagy is particularly important in post-mitotic cells such as those in the brain, heart, and skeletal muscle where very little cell regeneration via stem cells occurs. For mitotic tissues such as the GI tract, bone marrow, and skin, autophagy decline may not be as detrimental, since apoptosis is another normal method for getting rid of bad cells.
The failure of autophagy with aging has several possible causes:
a. Fusion problems – Autophagic vacuoles accumulate with age in the liver. This may be due to a problem of fusion between the autophagosomes and the lysosomes.
b. Glucagon deficiency – Glucagon is a hormone that enhances macroautophagy. “—the stimulatory effect of glucagon [on autophagy] is no longer observed in old animals. See item (b) in the next list below.(ref)“
c. Negative signaling via the Insulin receptor – Insulin activates the Insulin/IGF-1 pathway which activates mTOR. mTOR activation inhibits autophagy (see below). Even in the absence of insulin, there is up-regulation with aging of the insulin/IGF-1 signaling via the insulin receptor tyrosine kinase. This would activate mTOR.
d. Inadequate turnover of damaged mitochondria – Mitophagy decline may be one of the mechanisms that is responsible for the decline in autophagy with aging. Specifically, if mitophagy does not keep up with the demand for damaged mitochondrial clearance, a higher baseline ROS would occur, which would damage proteins, cell membrane lipids, and cell nucleus DNA.
e. Energy compromise – With aging, there is a decline in energy production by the cells. This may be one of the reasons for the decline in autophagy seen in aging.
Here is a depiction of some of the main problems associated with decline of autophagy in aging:
Some consequences of failure of autophagy with aging “Possible causes and consequences of the failure of macroautophagy in old organisms are depicted in this schematic model (brown boxes” Image source
(a) The accumulation of autophagic vacuoles with age could result from the inability of
lipofuscin- loaded lysosomes to fuse with autophagic vacuoles and degrade the sequestered content.
(b) In addition, the formation of autophagosomes in old cells might be reduced because of the inability of macroautophagy enhancers (such as glucagon) to induce full activation of this pathway. The stimulatory effect of glucagon is compromised in old cells because of maintained negative signaling through the insulin receptor (IR) even under basal conditions (i.e. in the absence of insulin). Maintained insulin signaling would activate mTOR, a known repressor of macroautophagy.
(c) Inadequate turnover of organelles, such as mitochondria, in aging cells could increase levels of free radicals that generate protein damage and
(d) Aging could also potentiate the inhibitory signaling through the insulin receptor.
(e) An age-dependent decline in macroautophagy can also result in energetic compromise of the aging cells.
5. Genetic manipulations that increase lifespan in all model organisms stimulate autophagy.
Knocking out macroautophagy takes away at least 50% of the long-lived mutant’s added lifespan. This same “loss of longevity” is seen with Caloric restriction in “macroautophagy knockouts”. The following diagram shows how important autophagy is in long-lived mutant nematodes and how this is important for increasing lifespan, reducing cellular damage, and increasing function.
The most well studied “mutants” are model organisms where one of the following pathways are altered by a gene mutation or a gene knock out. When an additional “knocking out” of an autophagy gene is done, approximately 1/2 of the added lifespan of the long lived mutants (vs wild type) appears to be “wiped out” by loosing autophagy. Similar findings occur in “macroautophagy knock-outs” subjected to caloric restriction, etc. This suggests to me that 1/2 of the benefits of caloric restriction are due to stimulating autophagy. Caloric restriction down regulates all of the”nutrient sensing pathways that are negative regulators of autophagy” and up regulates other “ nutrient sensing pathways that are positive regulators of autophagy”. The following interconnected “nutrient -sensing pathways” affect macroautophagy:
a. IGF-1: two mechanisms:
i. decreasing Insulin-IGF-1 pathway => tyrosine kinase => inhibits Akt phosphorylation of TSC => inhibition of raptor in mTOR complex
ii. decreasing insulin/IGF-1 pathway => Foxo transcription factor translocation to nucleus => FOXO stimulates autophagy via activating two autophagy genes – LC3 and BNIP3.
b. mTOR: three mechanisms account for the activation of autophagy by mTOR inhibition
i. mTOR inhibition => decreases phosphorylation of Atg1 (aka ULK1/2). Also decreases phosphorylation of Atg13 and Atg17. Phosphorylation of ULK1/2, Atg13, and Atg17 inhibits autophagy initiation.
ii. decreasing mTOR pathway => decreases phosphorylation of 4EBP1 => blocks effect of eIF4F => autophagy activation.
iii. decreasing mTOR pathway => decreases phosphorylation of S6K => S6K no longer active => inhibition of autophagy.
Signaling pathways that affect autophagy Image source
“The (mammalian) target of rapamycin (mTOR) is a primordial negative regulator of autophagy inorganisms from yeast to man. mTOR is inhibited under starvation conditions, and this contributes to starvation-induced autophagy via activation of mTOR targets Atg13, ULK1, and ULK2. This inhibition can be mimicked by mTOR inhibitory drugs like rapamycin (Ravikumar et al., 2010). One of the important pathways regulating mTOR is initiated when growth factors like insulin-like growth factor bind to insulin-like growth factor receptors (IGF1R) (Figure 2). These receptors signal, via their tyrosine kinase activities, to effectors like the insulin receptor substrates (IRS1 and IRS2), which in turn activate Akt. Akt inhibits the activity of the TSC1/TSC2 (proteins mutated in tuberous sclerosis) complex, a negative regulator of mTOR. In this way, IGF1R signaling activates mTOR and inhibits autophagy, and the converse occurs when nutrients are depleted(ref).”
c. Ras/PKA: decreasing Protein Kinase A pathway (aka Ras/cAMP) => decreases phosphorylation of 3 autophagy proteins (Atg1, Atg13, Atg18).
d. PKB/Akt: decreasing Protein Kinase B pathway (aka PkB/Akt or Sch9) => reduces inhibition of TSC-1 => decreased mTOR activity.
e. Sirtuin 1: CR activates Sirtuin 1 => deacetylation of several autophagy gene products: Atg5, Atg7, Atg8/LC3. Sirt1 also activates AMPK, activates FOXO3a, and inhibits mTOR via TSC-1/2
f. AMPK: AMPK pathway (aka LKB1-AMPK) activates autophagy via two methods:
i. AMPK activation => phosphorylates TSC2 and raptor => inhibits TORC1 (this requires glucose starvation).
ii. AMPK activation => direct phosphorylation of Atg1 (aka ULK1) => autophagy activation (this does NOT require glucose starvation).
g. Less-important pathways:
i. Rim15: increasing Rim15 Kinase pathway => Msn2 and Msn4 transcription factor translocation to nucleus => inhibits mTOR, PKA, and PKB pathways.
ii ERK1/2: ERK pathway – the extracellular signal-regulated kinase (ERK) also mediates starvation-induced autophagy. (see #6 below for more details)
iii. JNK: JNK pathway – This is a MAPK that mediates starvation-induced autophagy. (see #6 below for more details).
The main pathways are depicted in the following diagram of how Calorie Restriction works (Ras/PKA and less important pathways not depicted).
Autophagy regulation Image source
6. There are many other pathways that regulate autophagy that are not dependent on “nutrient sensing pathways.”
(i.e. not those described above).
Although caloric restriction or fasting are clearly the most “potent” autophagy stimulators, since they can activate macroautophagy via the above “nutrient sensing pathways“, there are many other pathways that can activate autophagy. Here an explanation of the roles of the key kianses involved:
a. PI3Ks and Akt – PI3Ks are kinases that are mainly activated by growth factors, not starvation. There are 3 classes of PI3Ks and the Class III PI3Ks directly positively activate autophagy (Vps34) whereas the Class I PI3Ks indirectly inhibit autophagy via mTOR and Akt.
b. MAPKs – Mitogen-Activated Protein Kinase – these are kinases that are mainly activated by growth factors, not starvation. There are 3 classes:
i. ERK – Extracellular signal-Regulated Kinases (ERK) positively regulate autophagy by maturing autophagic vacuoles. EKR also seems to specifically be involved with mitochondrial-specific autophagy (i.e. mitophagy). Mitochondrial ERK may help protect from neurodegenerative diseases. Cancer cells also activate mitochondrial ERK to cause chemoresistance. ERK is activated downstream from Ras. Ras activates Raf, which activates MEK. MEK phosphorylates and activates ERK1 and ERK2.
This is the mechanism by which you can kill cancer with soy extracts, capsaicin, and Cadmium. Here is how this works:
- Soyasaponins (found in soybeans) => activates ERK => autophagy-induced death in colon cancer cells
- Capsaicin (found in chili peppers) => activates ERK => autophagy-induced death in breast cancer cells
- Cadmium (toxic metal) => activates ERK => autophagy-induced death in mesangial cells
ii. p38 – p38 is a MAPK that is a tumor suppressor. p38 regulates autophagy but there is still controversy if it activates or inhibits autophagy.
iii. JNK – JNK is a MAPK that is activated by heat shock, osmotic shock, UV light, cytokines, starvation, T-cell receptor activation, neuronal excitotoxic stimulation, and ER stress. With starvation, JNK does not phosphorylate Bcl-2, which prevents it from binding to beclin 1. Beclin 1 can then induce autophagy. Bcl-2 is an anti-apoptotic protein and can prevent apoptosis. There are multiple phosphorylation sites on Bcl-2. The degree by which JNK phosphorylates/dephosphorylates Bcl-2 may determine cell fate – i.e. apoptosis (death) vs autophagy (survival). See (2011) The Beclin 1 network regulates autophagy and apoptosis.
c. PKC – Protein Kinase C (PKC) is a family of kinases that were once thought to be associated mostly with apoptosis/anti-apototis. Recent research has shown that PKCs also play a role in autophagy. The effects of PKC depend on if the cellular stress is acute or chronic. For instance, PKCg is an example of one of the PKCs where it stimulates autophagy with acute, short periods of hypoxia (via JNK activation) but suppresses autophagy with chronic hypoxia (via Caspace-3). Another PKC, PKC0 is involved with ER-stress induced autophagy. Acadesine (AICAR) induces autophagy via a PKC/Raf1/JNK pathway. Acadesine (AICAR) in combination with GW1516 has shown to improve endurance-type exercise by converting fast-twitch muscle fibers into the more energy-efficient, fat-burning, slow-twitch muscle fibers. These two compounds turned on 40% of the genes that were turned on when exercise + GW1516 were used together. For this reason, acadesine (AICAR) has been termed an “exercise mimetic” and has been banned for use by athletes, since it is a performance enhancing drug, even though it is very safe. The mechanism of action of AICAR may be in part its induction of autophagy.
d. Endoplasmic Reticulum Stress Kinases (i.e. the ER unfolded protein response) – Several kinases involved with the endoplasmic reticulum unfolded protein response (ER-UPR) have been found to activate autophagy. They include the following:
i. IRE-1 – Inositol-requiring enzyme (IRE1) is one of the first proteins activated by the ER-UPR. It up regulates autophagy genes (Atg5, 7, 8, 19).
ii. PERK – PERK must phosphorylate the eukaryotic initiation factor 2alpha (eIF2alpha) for LC3 conversion with ER-UPR induced autophagy. PERK also up regulates Atg5.
iii. CaMKKbeta – ER stress results in calcium release from the ER. This Ca++ release induces autophagy via the Ca dependent kinases. The main one is called Ca/Calmodulin-dependent kinase beta (CaMKKbeta). This is an “upstream activator” of AMPK, which in turn inhibits mTOR. This is how calcium can induce autophagy.
iv. DAPK1 – Death-associated protein kinase 1 (DAPK1) is another Ca++/Calmodulin-regulated kinase that is important in ER-UPR induced autophagy. It induces autophagy by phosphorylating beclin 1, which is necessary for autophagosome formation.
Mechanisms connecting ER stress and autophagyImage Source “Mechanisms connecting ER stress and autophagy. Different ER stresses lead to autophagy activation. Ca2+ release from the ER can stimulate different kinases that regulate autophagy. CaCMKK phosphorylates and activates AMPK which leads to mTORC1 inhibition; DAPK phosphorylates Beclin-1 promoting its dissociation from Bcl-2; PKCθ activation may also promote autophagy independently of mTORC1. Inositol 1,4,5-trisphosphate receptor (IP3R) interacts with Beclin-1. Pharmacological inhibition of IP3R may lead to autophagy in a -independent manner by stimulating its dissociation from Beclin-1. The IRE1 arm of ER stress leads to JNK activation and increased phosphorylation of Bcl-2 which promotes its dissociation from Beclin-1. Increased phosphorylation of eIF2 in response to different ER stress stimuli can lead to autophagy through ATF4-dependent increased expression of Atg12. Alternatively, ATF4 and the stress-regulated protein p8 promote the up-regulation of the pseudokinase TRB3 which leads to inhibition of the Akt/mTORC1 axis to stimulate autophagy(ref).”
7. Excess baseline ROS from bad mitochondria induces Mitophagy.
– ROS induces autophagy via a non-canonical pathway.
This may be the mitochondrial signal for “selective destruction” of damaged mitochondria. Exogenous ROS can also induce autophagy, however. For instance, there is evidence that abnormal levels of H202 in the cytoplasm will induce macroautophagy. Hydrogen peroxide induces a “non-canonical autophagy” that is “beclin-1 independent” but requires the JNK-mediated activation of Atg7. on of Atg7.
ROS induces autophagy: Roles of Akt, ERK, JNK and BeclinsImage source
8. Most all of the Pharmacologic manipulations that extend lifespan increase autophagy.
Here are some of the main ones:
a. Rapamycin – Autophagy explains most of the longevity and health benefits (mechanism of action) of Rapamycin
Since the protein kinase mTOR phosphorylates the 3 key autophagy initiating proteins (Atg1, Atg13, and Atg17), it is considered the “Master of Autophagy”. Rapamycin inhibits both TORC1 and TORC2. TORC1 inhibition is the the “direct” and primary mechanism by which rapamycin activates autophagy, but TORC2 inhibition has an “indirect” and independent method of activating autophagy via inhibiting Akt or Protein Kinase C. (This is why Blagonosky in NY likes rapamycin over TORC1-specific mTOR inhibitors).
Image source mTOR and autophagy, showing impacts of lithium and rapamycin
b. Metformin – .Autophagy may explain as much as 50% of the benefits (mechanism of action) of Metformin.
Metformin activates AMPK and therefore stimulates autophagy via TORC1-dependent and TORC-1 independent methods (see above). For this reason, metformin is a good “autophagy drug”. Metformin probably has many other mechanisms of action, however, which cannot be explained by the induction of autophagy.
c. Resveratrol – Resveratrol directly or indirectly activates the NAD+-dependent deacetylase, SIRT1.
SIRT1 activates autophagy by several different mechanisms, the 4 major ones being deacetylation of multiple cytoplasmic proteins including several involved with autophagy, such as ATG5, ATG7, and ATG8/LC3. SIRT1 also deacetylates the FOXO transcription factors (FOXO3a, FOXO, and FOXO4), but the FOXO proteins are not required for autophagy induction. It is likely that the effects of SIRT1 on FOXO deacetylation mediate other beneficial effects of resveratrol (not autophagy).
d. Spermidine – The benefits of spermidine can be partially explained by its effects on autophagy. Spermidine is a histone acetylase inhibitor. By inhibiting histone acetylase, spermidine allows for the up regulation of autophagy (Atg) genes. It appears that like resveratrol, spermidine also stimulates overlapping deacetylation reactions of cytoplasmic proteins. See the 2009 publication Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol.
Spermidine and autophagy in normal and diabetic states Image source
e. Lithium – The beneficial effects of Lithium for aging and for bipolar illness may be mediated in part by autophagy(ref).
9. Exercise can both activate and inhibit autophagy.
For this reason, the benefits of exercise are mostly due to non-autophagy factors.
Decreased autophagy mechanisms with exercise: Exercise up regulates mTOR, especially resistance exercises like weight lifting. Exercise also activates the IGF-1 pathway by increasing growth hormone secretion by the pituitary gland, which then in turn stimulates IGF-1 production by the liver. IGF-1 inhibits autophagy via the Insulin/IGF-1/PI3K/Akt pathway.
Increased autophagy mechanisms with exercise: ROS increases with exercise. Since ROS activates autophagy, this is one mechanism by which exercise could activate autophagy, but it is unclear if this activates “selective mitochondrial destruction” this way (i.e. mitophagy).
Hypoxia also activates autophagy via a HIF-1a pathway. This would occur with exercise if you reached your anaerobic threshold during exercise or did IHT exercise (intermittent hypoxia with exercise).
Conclusion: Exercise can both inhibit and activate autophagy. This may be why it is difficult to show exactly how exercise prolongs lifespan.
10. Autophagy exercises anti-aging effects on postmitotic cells.
– There are primarily 5 cytoprotective effects:
- Reduced accumulation of toxic protein aggregates, described above
- Destroying bad mitochondria via mitophagy, described above
- Reduced apoptosis
- Reduced necrosis
- Improved hormesis
Cells that do not divide are particularly vulnerable to the build-up of protein aggregates seen in neurodegenerative diseases. Autophagy inducers such as rapamycin, rapalogs, valproate, and lithium have been shown to help in experimental models of Huntington’s disease, tauopathies, Alzheimer’s disease, and Parkinson’s disease.
When mitochondria are defective due to ROS-induced damage, asymmetric fission occurs, allowing for a good mitochondria and a bad mitochondria to “split up”. The bad mitochondria has a low membrane potential and is tagged by PINK1 and then ubiquinated by Parkin. At this point, it is recognized by the autophagy system and is destroyed by macroautophagy.
Autophagy also has an anti-apoptotic function in post mitotic cells. Autophagy helps damaged cells recover and thereby avoid apoptosis. Autophagy also has an “anti-necrosis” function in post mitotic cells.
Autophagy is also a stress response involving hormesis. Hormesis is how low (sublethal) doses of cellular stressors result in an up regulation of cellular stress adaptation mechanisms. See the blog entries Multifactorial hormesis II – Powerpoint presentation and Multifactorial Hormesis – the theory and practice of maintaining health and longevity. Autophagy has a hormetic dose response curve. Depending on the strength or duration of the stressor, autophagy or a negative consequence could ensue, as exemplified in this diagram:
11. Anti-aging effects of Autophagy on Proliferating Cells
– Autophagy has cytoprotective effects and other unique effects in dividing cells:
- Cytoprotective effects – see #10 above
- Reduced stem cell attrition
- Reduced ROS-induced cellular senescence
- Reduced oncogenic transformation
- Improved genetic stability
- Increased p62 degradation
- Anti-cancer effects via increased oncogene-induced senescence and oncogene-induced apoptosis
With aging, there is a decline in bone marrow stem cell function (hematopoeitic stem cells and mesenchymal stem cells) and stem cell number (MSCs only). Rapamycin restores the self-renewal capability of hematopoietic stem cells (HSCs). This improves the function of the immune system, of course assuming a lower dose of rapamycin than the immunosuppressive rapamycin dose given for preventing organ transplant rejection. Rapamycin can also reverse the stem cell loss that occurs in hair follicles and thereby prevent alopecia. mTOR accelerates cellular senescence by increasing the expression of p16/INK4a, p19/Arf, and p21/Cip1. These are all markers of cellular senescence and up regulating these tumor suppressors induces cellular senescence.
The tumor suppressor PTEN is just the opposite, however. Loss of the tumor suppressor PTEN induces a unique type of cellular senescence called “PTEN loss-induced cellular senescence” (PICS). PICS occurs with mTOR activation and can be reduced by inhibiting MDM2, which leads to an increase in p53 expression. This would inhibit autophagy. Rapamycin can preclude permanent (irreversible) cell-cycle arrrest due to inducible p21 expression. In this aspect, mTOR decreases proliferative potential and mediates stem cell attrition via senescence. Rapamycin can suppress this. This effect may be mediated by autophagy or by an autophagy-independent effect of mTOR inhibition.
More importantly, several oncogenes suppress autophagy. This includes Akt1, PI3K, Bcl-2 family anti-apoptotic proteins. Most of the proteins that stimulate autophagy also inhibit oncogenesis. This includes DAPK1, PTEN, TSC1, TSC2, LKB1/STK11, and Beclin-1. Autophagy can suppress oncogenesis through cell-autonomous effects described below:
- Improved quality control of mitochondria (less baseline ROS production)
- Enhanced genetic stability
- Removal of potentially oncogenic protein p62 via autophagy.
- Autophagy up regulation results in oncogene-induced senescence (via Ras)
The diagram below shows the beneficial effects of autophagy on all cell types, specific benefits in proliferating cells, and specific benefits in post-mitotic cells.
Systemic Anti-Aging Effects of Autophagy Image source
12. Autophagy can reduce age-related dysfunction through systemic effects –
Autophagy also confers several beneficial anti-aging effects that are not due to cytoprotection, or other localized effects within the cell itself. This includes the following systemic benefits of autophagy:
- Defense against infections
- Innate immunity
- Inhibition of pro-inflammatory signaling
- Neuroendocrine effects of autophagy
Autophagy in dying antigen-presenting cells improves the presentation of the antigens to dendritic cells. In dendritic cells, autophagy improves antigen presentation to T cells. Autophagy in dying cells is also required for macrophage clearance of these dead/dying cells. This is how autophagy reduces inflammation. Autophagy helps keep ATP production going in these dying cells, providing energy for the key step in the lysophosphatidylcholine “find me” signaling as well as the phosphatidylserine “flip flop” that is the “eat me” recognition signal for macrophage ingestion of the dying/dead cells. By helping macrophages find these cells and recognize that they are ready for macrophage ingestion, these cells do not rupture and spill their intracytoplasmic contents (this is what causes the inflammation with necrosis, where cell membrane rupture occurs).
When autophagy is working hand-in-hand with apoptosis, no inflammation occurs when a cell dies. This is a key beneficial role of autophagy in reducing inflammation. The decline in autophagy seen in aging may be in part the cause of age-induced type-2 diabetes. Here the peripheral tissues become insulin resistant. This may be due to the hepatic suppression of the Atg7 gene, which results in ER stress and insulin resistance. Induction of autophagy in specific neural populations may be sufficiency to reduce pathological aging.
More effects of autophagy Image source
Beyond its cell-autonomous action, autophagy can reduce age-related dysfunctions through systemic effects. Autophagy may contribute to the clearance of intracellular pathogens and the function of antigen-presenting cells (left), reduce inflammation by several mechanisms (middle), or improve the function of neuroendocrine circuits (right).
13. Autophagy is necessary for maintaining the health of pools of adult stem cells
Frequent readers of this blog know that the writers believe that age-related decline of the health and differentiation capability of adult stem cells and increasing sensescence of those cells may be responsible for many of the effects we associate with aging. Thus, the positive roles of autophagy in keeping stem cells viable is of great interest to us.
See the comments under 11 above. Also, the June 2013 review publication Autophagy in stem cells provides “a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells.” Another such review is the June 2012 e-publication Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging.
Image Source “Tightrope act inhibition of mTOR via caloric restriction (CR) or rapamycin induces autophagy. Autophagy clears away damaged proteins and organelles like defective mitochondria, thereby decreasing ROS levels and reducing genomic damage and cellular senescence, thus playing a crucial role in enhancing stem cell longevity. CR may also have a role in maintaining low levels of p16ink4a, a tumor suppressor protein, thus reducing the risk of cancer and promoting proliferation of stem cells. Oncogenesis is countered by loss of PTEN which elicits a p53-dependent prosenescence response to decrease tumorigenesis(ref)”
Only now are studies beginning to emerge that characterize the detailed roles of autophagy in maintaining stem cell health and differentiation viability. Autophagy in stem cells recapitulates the current state of understanding: “As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.”
Another very-recent finding related to autophagy and stem cells is reported in the March 31, 2013 paper FIP200 is required for maintenance and differentiation of postnatal neural stem cells. “These data reveal that FIP200-mediated autophagy contributes to the maintenance and functions of NSCs through regulation of oxidative state.” FIP200 is “a gene essential for autophagy induction in mammalian cells.”
Exercising control over autophagy may prove useful for efficiently generating induced pluripotent stem cells. According to the 2012 publication Autophagy in stem cell maintenance and differentiation: “We also discuss a possible role for autophagy during cellular reprogramming and induced pluripotent stem (iPS) cell generation by taking advantage of ATP generation for chromatin remodeling enzyme activity and mitophagy. Finally, the significance of autophagy modulation is discussed in terms of augmenting efficiency of iPS cell generation and differentiation processes.”
A steady stream of research continues to reveal new insights on the roles that autophagy plays in stem cells. For example, the April 2013 publication FOXO3A directs a protective autophagy program in haematopoietic stem cells reports: “Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.”
14. Autophagy is a key step in activating the Nrf2 pathway. And Nrf2 expression can in turn regulate autophagy.
The importance of the Nrf2 stress-response pathway and its role in generating health has been one of the frequent topics of discussion in this blog. See specifically the blog entries The pivotal role of Nrf2. Part 1, Part 2, Part 3, and Nrf2 and cancer chemoprevention by phytochemicals. We know now that autophagy plays a key role in Nrf2 activation, via p62-dependent autophagic degradation of Keap1. See, for example, the 2012 publication Sestrins Activate Nrf2 by Promoting p62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver Damage. We also know that, in turn, Nrf2 expression can regulate autophagy. See for example the March 2013 publication Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2.
15. Autophagy and aging
We are starting to understand why autophagy stops working well when a person grows old – why autophagy does not work as well as you age. Among the reasons are:
a. Failure to form autophagosomes – with aging, there appears to be a failure for autophagosomes to form, possibly due to macroautophagy enhancers (glucagon).
b. Failure of fusion – with aging, there appears to be a failure of lysosomes to fuse with autophagosomes.
c. Negative signaling from insulin or insulin receptors – with aging, insulin signaling or insulin receptor signaling activates mTOR in cells.
d. Mitophagy does not work as well in aging.
e. Autophagy decline probably also results in energy (ATP production) decline.
16. Practical interventions to promote autophagy
There are a number of practical ways to promote autophagy. Specifically, in partial recap of the above:
- Fasting activates Autophagy – caloric restriction affects 5 molecular pathways that activate autophagy
- Sunlight, Vitamin D and Klotho activate Autophagy – there are three ways through which UV light, Vitamin D, and the Klotho pathway activate autophagy via inhibiting the insulin/IGF-1 pathway
- Rapamycin activates Autophagy – there are two ways through which mTOR inhibitors activate autophagy – TORC1 and TORC2 mechanisms
- Caffeine activates Autophagy – Caffeine can activate autophagy via an mTOR-dependent mechanism
- Green tea activates Autophagy – ECGC can activate autophagy via an mTOR-dependent mechanism
- Metformin activates Autophagy – metformin can activate autophagy via AMPK activation – mTOR-dependent and mTOR-independent mechanisms
- Lithium activates Autophagy – lithium and other compounds can activate autophagy by inhibiting inositol monophosphate and lower IP3 levels – an mTOR-independent mechanism
- Resveratrol activates Autophagy – there are four 4 ways through which resveratrol can activate autophagy – via mTOR-dependent and mTOR-independent mechanisms
- Spermidine activates Autophagy – how spermidine activates autophagy via histone protein deacetylation – mTOR-indepdendent mechanism
- Hypoxia activates Autophagy – intermittent hypoxia can increase autophagy via HIF-1a
- Phytosubstances which activate the Nrf2 pathway can activate Autophagy. These are many and include soy products and hot chili peppers.
In addition, these lesser-known substances can also activate autophagy:
Amiodarone low dose Cytoplasm – midstream yes Calcium channel blocker => TORC1 inhibition. Also, a mTOR-independent autophagy inducer
- Fluspirilene low dose Cytoplasm – midstream yes Dopamine antagnoists => mTOR-dependent autophagy induction
- Penitrem A low dose Cytoplasm – midstream yes high conductance Ca++activated K+ channel inhibitor => mTOR-dependent autophagy inducer
- Perihexilenelowdose Cytoplasm- midstream yes 1. TORC1 inhibition
- Niclosamidelowdose Cytoplasm- midstream yes 1. TORC1 inhibition
- Trehalose 100 mM Cytoplasm – midstream supplement 1. activates autophagy via an mTOR-independent mechanism
- Torin-1 low dose Cytoplasm – midstream no 1. mTOR inhibition (much more potent than rapamycin)
- Trifluoperazine low dose Cytoplasm – midstream yes Dopamine antagonists => mTOR-dependent autophagy induction
Wrapping it up
Here are some of the main points above covered:
- Autophagy is like having a Pac man inside each of your cells, chasing down, eating up and recycling dysfunctional organelles, proteins and protein aggregates. It has three forms: i. chaperone-mediated autophagy, ii. microautophagy and iii. macroautophagy. The last is the most important one.
- Autophagy is a stress response and behaves according to the principles of hormesis.
- Autophagy can retire and eat up old mitochondria which have become electron-leaking engines.
- Autophagy solves the problem of high baseline levels of reactive oxygen and nitrogen species.
- Autophagy does not require proteins to be unfolded for it to work and therefore can perform housekeeping tasks undoable by the other cell-level house cleaning system, the ubiquitin-proteasome system.
- Autophagy gets rid of the protein aggregates that can make you loose your memory or walk slow as you grow old – those associated with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, CTE, and other neurodegenerative conditions.
- Autophagy keeps adult stem cells healthy and facilitates their capability to differentiate to make normal somatic body cells.
- Autophagy prevents inflammation – it works hand-in-hand with apoptosis to help the body get rid of dying cells without inducing cell rupture and inflammation.
- Autophagy prevents cancer – it helps maintain genetic stability, prevents epigenetic gene silencing. And it helps promote oncogene-induced cellular senescence for cancer prevention.
- Autophagy saves the lives of cells by preventing unnecessary cellular apoptosis and cell necrosis.
- Autophagy is involved in Nrf2 activation and to some extent Nrf2 expression negatively regulates autophagy.
- Autophagy keeps your bone marrow stem cell population alive and functional.
- Autophagy helps with infections – it helps clear intracellular pathogens such as bacteria and viruses.
- Autophagy improves the innate immune response.
- We are starting to understand why autophagy declines with aging.
- While autophagy declines with aging, it can exercise multiple effects to slow aging down. It inhibits the major mechanisms of aging such as cellular senescence, protein aggregate build-up, stem cell loss, epigenetic gene silencing, telomere shortening, and oxidative damage to proteins, lipids, and DNA.
- There are many practical ways to activate Autophagy like consuming green tea and caffeine, and some less-practical ones.
A simple, comprehensive plan to prevent or reverse Alzheimer’s Disease and other neurodegenerative diseases – Part 1: The Plan | AGINGSCIENCES™ – Anti-Aging Firewalls™Author: SupremePundit
A simple, comprehensive plan to prevent or reverse Alzheimer’s Disease and other neurodegenerative diseases – Part 1: The Plan
By James P Watson, with contributions and editorial assistance by Vince Giuliano
INTRODUCTION AND OVERALL PRINCIPLES
This is the first of a pair of blog entries concerned with dementias – neurological diseases including Alzheimer’s Disease (AD) and its cousins. This Part 1 write-up was inspired by a recent small, non-randomized clinical trial done by Dr. Dale Bredesen that showed true “Reversal of Cognitive Decline” in 9 out of 10 patients with documented cognitive decline (Bredesen, 2014). Not all of these patients had AD, but all had cognitive decline. Five had AD, two had SCI (subjective cognitive impairment), and two had MCI (mild cognitive impairment). Although this study was too small to allow any statistical conclusions, it is the most positive report in a series of disappointing reports on the recent failures of Big Pharma’s monoclonal antibodies against amyloid-beta. Dale Bredesen’s approach was a multifactorial one – utilizing 24 different approaches to halt or reverse cognitive decline. We explore those 25 interventions here, focusing on the first 19. They do not depend on drugs. The focus of this blog entry is “What can be done about dementias now?”
The forthcoming Part 2 blog entry will provides a detailed discussion of some of the key science related to AD and dementias. This is the “What is science telling us about dementias?” part which gets quite complex. We review major theories related to AD there including the Hardy Hypothesis related to amloid beta, the GSK3 theory and more detail on the neuroinflammation theory which we introduce in this Part 1 blog entry. We expect to emphasize the emerging importance APP (Amloid Precursor Protein). And we will describe some very recent research that appears to establish that a basic cause of AD is the proliferation in aging of vestigal DNA segments in our genomes (known as LINEs which are long interspersed nuclear elements and SINEs which are short interspersed nuclear elements) with encode over and over again for the production of APP and for the failure of its clearance. This could well finally explain the role of beta amyloid in AD.
We have published a number of earlier blog entries relating to AD and dementias. For example, you might want to review my August 2014 blog entry The Amyloid Beta face of Alzheimer’s Disease.
Dementia only happens to a minority of the population with aging, but is becoming an ever increasing problem with the explosion in longevity occurring world-wide
Cognitive decline is the major “fear” people have of getting old. Even individuals with the feared “ApoE4 polymorphism” are not “predestined” to develop Alzheimer’s Disease (AD). The ApoE4 allele is only a “risk factor” for AD, not the cause of AD.
A common error is that most people view “dementia” and “Alzheimer’s disease” as synonyms, but this is incorrect. Alzheimer’s disease is only responsible for 60% of cases of dementia in the US and even less of the cases in Japan. In the US, Vascular Dementia (VaD) is the second-most common cause of dementia (20%), whereas in Japan, the incidence of AD and VaD is almost the same. In the US, the remaining 20% of dementia cases are due to several other neurodegenerative diseases such as Lewy Body Dementia (LBD), Parkinson’s disease with dementia (PDwithD), Frontotemporal dementia/ALS spectrum disorder (FTD/ALS), and mixed dementia (which is usually a mixture of AD and VaD).
A portrayal of the breakdown follows.
In the Middle East and China, VaD is more common than AD. This was true in Japan two decades ago, but now the ratio of AD to VaD is 1:1. Since AD and VaD are clearly the leading causes of dementia world-wide, we will focus mostly on these two types of dementia. Also, the risk factors for AD and VaD overlap and there are cases of “mixed dementia” which include features of both diseases. AD affects 5.4 million Americans and 30 million globally. By 2050, these numbers will be 13 million (US) and 160 million (world-wide) (Ferri, 2005). Many experts now regard dementia from neurodegenerative diseases as the 3rd leading cause of death after cardiovascular disease and cancer. Despite millions of dollars being spent annually on research, the exact causes of these dementias are still unknown, but the number of clues to the causes is growing and we will explore some of the main ones in our Part 2 blog entry.
Neuroinflammation is the most universally accepted explanation for AD
What is clear is that the “universal sign” of all neurodegenerative disease is “neuroinflammation”, which under the microscope is manifested as “gliosis” and is seen with AD, VaD, PD, FTD/ALS, and the type of dementia seen after multiple concussions, which is now called “Chronic Traumatic Encephalopathy” (CTE). Although they all have different “triggers” for each disease, they all have “neuroinflammation” and histologic signs of gliosis. We return to neuroinflammation several times as a central theme here and in the Part 2 blog entries.
Another “universal feature” is that all of these disease have familial cases with as few as 5% being genetic (AD) and as many as 50% being genetic (FTD). In these familial cases, there is most often a genetic mutation that is causal in nature (early onset disease) or a single nucleotide polymorphism (SNP) that is not causal in nature, but predisposes the patient to the disease. With the exception of CTE (where the primary cause is multiple concussions) and PD (where pesticide exposure, family history of PD, and depression combine to produce an odds ratio OR = 12.0), most of the cases of neurodegenerative dementias remain largely sporadic with unknown specific causation.
Environmental risk factors for neurodegenerative diseases are discussed in the 2005 publication Neurodegenerative Diseases: An Overview of Environmental Risk Factors and in publications in this list.
Despite millions of dollars being spent annually on research, the exact cause of these dementias are still unknown, but the number of clues to the cause is growing. What is clear is that the “universal sign” of these neurodegenerative diseases is “neuroinflammation”, which under the microscope is manifested as “gliosis” and is seen with AD, VaD, PD, FTD/ALS, and the type of dementia seen after multiple concussions, which is now called “Chronic Traumatic Encephalopathy” (CTE). Although they all have different “triggers” for each disease, they all have “neuroinflammation” and histologic signs of gliosis. Another “universal feature” is that all of these disease have familial cases with as few as 5% being genetic (AD) and as many as 50% being genetic (FTD). In these familial cases, there is most often a genetic mutation that is causal in nature (early onset disease) or a single nucleotide polymorphism (SNP) that is not causal in nature, but predisposes the patient to the disease.
With the exception of CTE (where the primary cause is multiple concussions) and PD (where pesticide exposure, family history of PD, and depression combine to produce an odds ratio OR = 12.0), most of the cases of neurodegenerative dementias remain largely sporadic with unknown specific causation.
Failure of Monotherapeutic Approaches to Neurodegeneration – It is time to consider multiple component therapies
The development of drugs to treat neurodegeneration has probably been the biggest failure of the pharmaceutical industry. Although there are three FDA-approved drugs for AD, none of them produce anything other than a marginal, unsustained effect on symptoms. Hundreds of clinical trials for AD have failed over the past two decades, most recently being the large Phase III trials of monoclonal antibodies that target amyloid-beta. As of today, no drugs have been approved for Frontotemporal dementia, Vascular dementia, and Lewy body dementia. Only one drug has been approved for Amyotrophic lateral sclerosis (ALS). All of the clinical trials done for these diseases have largely been with monotherapeutic drug approaches.
We know from the field of cardiovascular disease, cancer, and HIV that single drug therapy for these diseases largely fail. . It is now clear that cancer is “incurable” with chemotherapy unless multiple drugs are used. Combination therapies have become the standard for treating these conditions. The requirement to combine drug therapies appears to pertain as well to diseases that we cannot “cure” but that are are yet treatable: we can control the disease and prevent premature death from the disease. This includes cardiovascular disease, HIV, and a few other glaring chronic diseases. These diseases like dementias involve simultaneous upregulation or downregulation of hundreds or thousands of genes including protein-producing ones, and simultaneous activation or inhibition of a large multiplicity of pathway. It is a very tall order to find a single molecule that can have the right effects on so very many different upregulated and downregulated molecules and pathways at the same time. Yet, Big Pharma by tradition and because of patent law likes to look for single molecules that can be patented and that can make a big differences in a key step in a highly specific disease processes. But most serious aging-related diseases and dementias don’t offer such an opportunity.
The Multi-factorial approach rather than “single target” approaches to Treating Alzheimer’s Disease
For the same reasons, it makes sense that a single drug made by “Big Pharma” could NOT solve the problems with these neurodegenerative diseases. Here is a list of 25 different interventions that were combined into one effective program that “reversed” AD in 9 of 10 patients treated in a pilot study at UCLA and the Buck Institute. None of these involve drugs. I will include in black, the ones that were recommended by Dr. Dale Bredesen in what he calls the “MEND” program, which is an acronym that stands for “Metabolic Enhancement for NeuroDegeneration”. You can check out his 2014 paper Reversal of cognitive decline: A novel therapeutic program.
SECTION I PRACTICAL INTERVENTIONS
1. Eat a low glycemic, low inflammatory, low grain diet – Since sugar triggers insulin release and the insulin receptor triggers brain aging, this is easy to understand. For several complex reasons, certain proteins found only in grains (such as wheat germ, wheat gliadins) also triggers inflammation. The foods that have a high glycemic index or have lots of wheat in them include the following:
|High glycemic index foods (these are bad) (and pro-inflammatory nonglycemic foods)||Low glycemic index foods (these are good) (and anti-inflammatory foods and beverages)|
|Sweet Fruit – banannas, oranges, grapefuit||Fatty fruit – avocadoes, olives, capers|
|Orange juice, Apple juice, grape juice||Unsweetened coconut milk, soymilk, almond milk|
|Pancakes, waffles, French toast, toast||Scrambled eggs, omelettes, boiled eggs, fried eggs|
|Candy, Pies, Cake, Ice cream, Sherbert||Vegetables – Broccoli, Brussel sprouts, Artichokes|
|Corn bread, Cornflakes, corn oil||Olive oil, Coconut oil extract (MCT oil)|
|Processed cold cereals – Chex, Raisin bran||Oatmeal, barley cereal, rye bread, etc.|
|Cream of wheat, Fruit loops, etc.||Mushrooms, seaweed (Sushi), cheese, butter|
|Toast, bread, donuts, bagels, croissants||tomato soup (add some protein), mushroom soup|
|Potatoes, potato chips, French fries||Cream of broccoli soup, lentils, legumes|
|Sweetened yogurt, sweetened milk||Unsweetened yogurt, Greek yogurt|
|Cow’s milk, Chocolate milk, hot cocoa||Prosage patties, garden burgers, vegelinks|
|Jam, jelly, honey, maple syrup, pancake syrup||Soymeat, tofu, vegameat, Frichick|
|Peanut butter, Jam, and bread sandwiches||Portobello mushroom sandwiches w/o bread|
|White rice, brown rice, pita bread, wild rice||Indian curries (leave out the potatoes), Thai curry|
|Wheat thins, Pretzels, wheat snacks||Dried kale chips, seaweed snacks, onion snacks|
|Sugar drinks, sweetened tea, Gatoraid||Green tea, white tea (no caffeine), herbal teas|
2. Enhance autophagy – This can be done without fasting all day. Research has shown that fasting for at least 12 hours per day (evening and night) is sufficient to activate autophagy. Not eating for at least 3 hours before bedtime also activates autophagy. Eating the evening meal earlier in the day also helps. For those who do not want to fast for at least 12 hours, there may be little hope of “cleaning the cobwebs out of the brain”. Studies have shown that eating too much or eating late at night completely shuts off autophagy. This is probably the #1 reason why most people have so much “proteotoxicity” in the brain, the pancreas, and other organs. You can review our blog entry Autophagy – the housekeeper in every cell that fights aging.
There are some natural compounds and some drugs that stimulate autophagy, however. They include the following:
- mTOR inhibitors – The mTOR pathway is “downstream” from the Insulin/IGF-1 pathway. The mTOR pathway completely “shuts off” autophagy and stimulates protein synthesis. This is the primary “danger” of eating too much meat or protein (i.e. stimulating the mTOR pathway). Continually inhibiting the mTOR pathway is probably not a good idea either, since it is very important to synthesize proteins. However, intermittent mTOR pathway inhibition has been shown to be a very effective way of stimulating “cellular housekeeping” in the brain. The best-known drug that inhibits the mTOR pathway ia rapamycin. Low glucose levels and low amino acid levels in the blood also inhibit mTOR. It is interesting that at least one big pharma company, Novartis, is interested in marketing rapamycin as an anti-aging drug(ref).
- AMPK activators – The AMPK pathway is one of the major pathways that activates autophagy. AMPK is activated by both exercise and fasting. The AMPK pathway is a “cross-talk” pathway between mTOR and the Insulin/IGF-1 pathway. Activating AMPK inhibits both of these “bad” pathways. (They are only bad in certain contexts of aging and still serve important functions in aging people. We could not be alive without them. In the Part 2 blog entry we will talk about how some times IGF is the good guy we don’t want to be without.) Besides exercise and fasting, AMPK can be stimulated by three hormones, some drugs and many natural compounds. The most potent AMPK activator is muscle contraction (i.e. exercise). The three hormones that stimulate AMPK are thyroid hormone and two hormones secreted from fat: leptin and adiponectin. Next to this, the most potent chemical activators of AMPK are probably AICAR and ZMP. These are synthetic compounds that are the only true “exercise mimetics”. ZMP is a derivative of AICAR. AICAR has been shown to increase endurance in rodents by 44% without exercise. This is amazing. Combining AICAR with exercise makes the drug even more effective. Unfortunately, AICAR is very expensive ($350-450/gram). Common drugs that activate AMPK include metformin and aspirin. Natural compounds that activated AMPK include resveratrol, pterostilbene, curcumin, EGCG, betulinic acid, Gynostemma Pentaphyllum, Trans-Tiliroside (from rose hips), and 3-phosphoglycerate. See this list for articles in this blog that deal with autophagy or describe autophagy activators.
- Sirtuin activators – The 3rd major family of pathways that activates autophagy is for the Sirtuin enzymes (SIRT1-7). Sirtuins are enzymes that remove acetyl groups from proteins. The most important ones it deacetylates for autophagy are 3 proteins that are crucial to the autophagy system of “cellular housekeeping”. These 3 proteins are Atg5, Atg7, and Atg8. There are many practical reasons why activating Sirtuin-induced autophagy is critical to health. For instance, SIRT1 activation protects cells in human degenerative discs from death by promoting autophagy. This is why fasting has been shown to eliminate back pain. The most well-known SIRT1 activator is resveratrol, the active ingredient in red wine. However, both red wine and white wine have been shown to activate Sirtuin enzymes. NAD+, NMN, and NR all activate Sirtuin enzymes (all 7 of them), whereas resveratrol only activates SIRT1. You can see our blog entry NAD+ an emerging framework for health and life extension — Part 1: The NAD World
3. Reduce stress – psychological stress, depression, worrying, and being obsessive compulsive all increase the risk of Alzheimer’s disease. The most effective ways to reduce “cellular stress” are as follows:
- Yoga – yoga has been scientifically proven to reduce stress. The mechanism may be multifactorial, but studies suggest that activating stretch receptors in the muscles induces the SIRT3 gene. The Sirtuin pathway is a major pathway activated by fasting, caloric restriction, red wine, NAD+, NMN, NR, and certain other natural compounds.
- Meditation – meditation has been scientifically prove to reduce stress. However, 3 minutes of prayer is NOT meditation. Meditation requires 30-60 minutes of time. The MEND program recommends 20 minutes of meditation twice a day (No one prays that long).
- Tai chi – this ancient Chinese form of exercise has been shown to reduce stress
- Exercise followed by rest – exercise alone does not reduce stress, but exercise followed by a good night’s rest is very effective at reducing stress
- Stretching exercises – These have a special beneficial effect on stress, especially back stretching exercises for back pain.
Self-monitoring of daily stress and exercise can be helpful for knowing what your stress levels are and how good a job you are doing at keeping stress at non-harmful levels. A great many of the upstream conditions that can lead to dementias mentioned here (sedentary life style, improper diet, inadequate sleep, etc) are likely to induce constitutional stress which can be picked up by such monitoring. A host of new wearable devices can keep track of exercise and its consequences. See the blog entry Digital health – health and fitness wearables, apps and platforms – implications for assessing health and longevity interventions – Part 1. Vince has identified two constitutional stress measurements in his blog entry that can be tracked starting with smartwatch heart rate and sleep measurements, MRHR (morning resting heart rate before awakening), and ERHR-MRHR (difference between evening resting heart rate and morning resting heart rate during sleep, a measure of overnight sleep-related constitutional stress recovery),. These are described in the blog entry Digital health – health and fitness wearables, Part 2: looking for practical stress biomarkers. Also, heart rate variability is another personally trackable constitutional measurement of stress, See my recent blog entry on heart rate variability, Digital Health Part 3.
4. Optimize sleep – At least 8 hours of sleep at night is very effective in preventing Alzheimer’s disease.
Daytime sleeping probably is not as effective, but is probably not harmful provided that a person is not too sedentary with daytime sleeping (i.e. short naps). Adding 0.5 – 3 mg of melatonin and 500 mg of tryptophan is also very helpful in getting a good night’s sleep. One of the biggest problems with getting a good night’s sleep is sleep apnea, which is actually very common as we get older.
“A Simplified schematic of the proposed interventions that may have potential to delay AD pathogenesis — The green arrows indicate pathways for improved circadian regulation and sleep quality, ultimately delaying AD pathogenesis. According to this model, chronobiotics (i.e., bright light therapy (BLT); melatonin; exercise; and food restriction) and good sleep hygiene could be used individually—but preferably in combination—to improve circadian regulation and sleep quality, decrease inflammation and Aβ deposition, and thereby delay AD pathogenesis.” Image and legend source
5. Exercise – The World Health Organization recommends 150 minutes of exercise per week, but the best scientific evidence suggests that this is NOT enough. The best scientific evidence suggests at least 450 minutes of exercise per week. That is 60 minutes per day and an extra 20 minutes on one of those days. If you want to skip Saturday, that means 75 minutes per day (1hr 15 minutes). The exercise should include the following for preventing Alzheimer’s disease:
- Swimming, outdoor hiking, calisthenics, aerobic fitness classes, spinning classes, etc.
- 30-45 minutes of aerobic exercise where the heart rate is 60% of training heart rate. This can be on a stationary bicycle, an elipical machine, a “hand bicycle”, a stair climber,
- 1 mile per day of walking outside (the speed is not important)
- Resistance exercise – this includes weight lifting, machines, stretch bands, push-ups, etc.
- Stretching – stretching activates stretch receptors which activates the SIRT3 gene, which is key for mitochondrial function and decreasing free radicals in the muscles (which cause pain
- Listening to relaxing music – classical music listening is a good way to relax.
Watching TV or looking at a computer screen and “surfing on the computer” probably does NOT work to reduce cellular stress. Here are some of the blog entries we have published relating to exercise.
6. Brain stimulation – The Mayo Clinic did a study in 487 patients where they participated in a computerized cognitive training program called “Brain Fitness Program” by Posit Science. This computer training required 1 hour of time per day, 5 days per week for 8 weeks (totaling 40 hours). This was called the IMPACT study. This program increased their auditory processing speed by 131% and improved their memory an equivalent of approximately 10 years! Here is some information on this inexpensive computer program:
- Posit Science Brain Fitness Program for One Person
- PositScience Brain Fitness Program Classic (PC Version)
Some of us think that we may keep our brains fit by constantly trying to figure out the mechanisms of aging.
7. Keep your homocysteine low – High homocysteine levels seem to correlate with inflammation and also with deficiencies in folate cycle intermediates. The MEND program recommendation is to check your homocysteine levels and if it is > 7, then to take methyl-B12, methyltetrahydrofolate, pyridoxal-5-phosphate, and trimethylglycine (if necessary). The dosages are: Methyltetrahydrofolate – 0.8 mg/day and Pyridoxine-5-phosphate – 50 mg/day
8. Keep your vitamin B12 high – Vitamin B12 is very important in memory and prevention of dementia. Vit B12 deficiency alone can cause dementia. It is easier to prevent than to reverse. The MEND program recommends taking methyl-B12, not regular B12. They recommend basing the dose of methyl-B12 on serum levels of B12, which they recommend keeping above 500 with 1mg of methylB12/day.
9. Keep your C-reactive protein low – CRP is a measure of inflammation. This correlates very well with inflammation in the brain (called neuroinflammation). They recommend keeping the CRP levels below 1.0 and the Albumin/globulin ratio > 1.5. There are no FDA-approved drugs that lower this which are safe to be used on a chronic basis. However, there are several natural products that are effective in reducing C-reactive protein (CRP). They include curcumin (400 mg/day), Fish oil (DHA & EPA), and an anti-inflammatory diet that is low in sugar and wheat products. The MEND program recommends 700 mg of DHA twice a day (total 1400 mg) and 500 mg of EPA twice a day (total 1,000 mg). Since most Fish oil capsules are only about 1/3rd omega-3 fatty acids, that means you need to take about 7,000-8,000 mg (i.e. 7-8 one gram capsules) per day of Fish oil.
10. Keep your fasting insulin low – Most people develop insulin resistance with aging. Unfortunately, this is rarely diagnosed until they have already suffered the consequences of insulin resistance, which include metabolic syndrome, hypertriglyceridemia, hypercholesterolemia, Alzheimer’s disease osteoarthritis, accelerated hearing loss, accelerated visual impairment (including presbyopia, cataracts, and age-related macular degeneration, aka AMD). Once these things occur, then reducing your fasting insulin no longer is useful – the cells are already dead! The MEND program recommends keeping your fasting insulin to < 7.0. The best way to do this is to eat a low glycemic index diet, encourage ketogenesis by 12 hours of fasting per day, exercise, sleep, and in some cases the drug metformin. We have found that the NAD precursor, NMN is effective in reducing fasting insulin levels. Other supplements designed to enhance NAD+ may help as well.
11. Hormone balancing – The MEND program recommends normalizing thyroid hormone levels (free T3, free T4, estrogen, testosterone, progesterone, pregnenolone, and cortisol). For most people, cortisol levels are way too high. The best way to reduce cortisol is to reduce stress, improve sleep, and also possibly to supplement with NMN or NR. The rest of the hormones decline with aging and often need replacement. Here are some ways to make this safe:
- Testosterone replacement therapy – this is risky in older men, due to the risks of accelerated coronary artery narrowing due to neointimal hyperplasia, as well as benign prostatic hypertrophy worsening or by making prostate cancer grow. For this reason, a thorough work-up for prostate cancer must be done before starting testosterone. In addition, testosterone dosing should be based on testosterone levels.
- Progesterone – This is primarily for women, but also helps men in low doses. Any progesterone replacement therapy should also be based on blood levels of progesterone.
- Pregnenolone – This helps both men and women for the brain.
- Estradiol (E2) – This should also be done based on blood levels of E2
12. Healthy gut bacteria – Most people have very unhealthy gut bacteria due to the use of antibiotics, due to general anesthesia, and due to dietary factors such as a high sugar diet. As a result, the lactobacillus that are good for your health often die. In addition, the fiber-fermenting bacteria are often absent, thereby eliminating the healthful effects of a high fiber diet. Probiotics and prebiotics are often helpful in restoring healthy gut bacteria. You can see Vince’s 2012 blog entry Gut microbiota, probiotics, prebiotics and synbiotics – keys to health and longevity.
13. Reducing amyloid beta aggregates – One of the hallmarks of Alzheimer’s disease is the accumulation of misfolded, aggregates of a protein called amyloid beta. Fortunately, there are two natural compounds that if taken in large quantities can reduce amyloid-beta plaques in the brain. They are Ashwagandha and curcumin. Both of these are effective in reducing amyloid beta plaques. The MEND program recommend doses of 500 mg for Ashwagandha and 400 mg for curcumin. Because curcumin is so poorly absorbed, it is better to take a liposomal or nanoparticle form of the curcumin, like Bio-curcumin 95. Curcumin can be taking as a pill, but it may be absorbed much better in curry that has coconut oil, since the coconut oil creates an emultion and micelles which can be absorbed by the lymphatic system and thereby “bypass” the liver and the “first pass effect”. Ashwagandha is much better absorbed and does not have as much of a problem. It can be taken as a pill, but also can be taken as a tea. My friend Dr. Vince Giuliano has made a liposomal form of these two compounds together with two complementary anti-inflammatory herbal extracts which he believes get into the blood stream in concentrations that are 8-10 times higher than by pill form. He has written about these and other phytosubstances a number of times, e.g.(ref) (ref) (ref) (ref) (ref).
14. Cognitive enhancement – This category was probably added to the MEND program for supplements that could not be categorized elsewhere. They specifically recommend the natural product called Bacopa monniera and Magnesium. Bacopa monnieri is also called “water hyssop”, “herb of grace”, “Indian pennywort” and Withania somnifera. Bacopa monniera has been shown to reduce amyloid plaque and prevent synaptic decline in mouse models of AD. One possible mechanism by which Bacopa monnieri works is to enhance LDL receptor-related protein, which is the “amyloid exporter” in the brain. There are many studies that show a benefit from Bacopa monniera In humans. A meta-analysis of 6 high quality clinical trials of Bacopa monniera showed that 9 out of 17 tests showed improved performance in the domain of “memory free recall”. In a study on Okadaic acid induced memory impaired rats, the effect of standardized extract of Bacopa monnieri and Melatonin on the Nrf2 pathway was investigated. “OKA caused a significant memory deficit with oxidative stress, neuroinflammation, and neuronal loss which was concomitant with attenuated expression of Nrf2, HO1, and GCLC. Treatment with BM and Melatonin significantly improved memory dysfunction in OKA rats as shown by decreased latency time and path length. The treatments also restored Nrf2, HO1, and GCLC expressions and decreased oxidative stress, neuroinflammation, and neuronal loss. Thus strengthening the endogenous defense through Nrf2 modulation plays a key role in the protective effect of BM and Melatonin in OKA induced memory impairment in rats.” There is a special form of magnesium which is much better incorporated into the cell called Magnesium-L-threonate, aka MgT. Both can be taken as a capsule. The dose Bacopa monniera they recommend is 250 mg/day. However, most of the clinical trials recommend dosages of 300-450 mg/day.
15. Vitamin D3 –Vitamin D3 seems to be quite different than the other vitamins for a variety of reasons. The most important difference is that Vitamin D levels should be checked and individuals need to adjust their dose based on their serum vitamin D3 levels. To prevent AD, the levels of Vitamin D3 need to be > 50 nmol/L. The strongest evidence for this comes from two recent studies from 2014. One was a 5 year study in 1,658 elderly patients who started the study with no dementia. During the 5 years, 171 of the 1,658 developed dementia (10% risk over 5 years). This study looked at “all cause dementia”, of which 90% is Alzheimer’s dementia (AD) and Vascular dementia (VD). The risk of developing dementia when serum Vitamin D3 levels were > 50 nmol/L was very low. However, those with Vit D3 levels between 25 and 50 nmol/L had a 1.53 fold higher risk of developing dementia of any type. Those with levels below 25 nmol/L had a 2.25 nmol higher risk of developing dementia of any type. The 2nd study reported in 2014 was from Denmark and followed 10,186 individuals in the Danish population for 30 years. They looked at the risk of specific kinds of dementia and the relationship to Vitamin D3. For Alzheimer’s disease (AD), the risk of AD type dementia was 1.25-1.29 fold higher in those with serum Vit D3 levels below 25 nmol/L. For Vascular Dementia (VD), the risk of VD type dementia was 1.22 fold higher in those with serum Vit D3 levels below 25 nmol/L. In conclusion, low Vitamin D3 levels is one of the largest risk factors for dementia and the easiest to prevent. Most people do not get their Vitamin D3 levels checked. Do you know what yours is?
16. Increasing Nerve Growth Factor (NGF) – Hericium erinaceus and ALCAR — Although there are many growth factors that make nerve cells grow, the most important one is probably Nerve Growth Factor (NGF). NGF is a growth factor made and secreted by astrocytes in the brain and spinal cord. NGF enhances neuronal stem cell regeneration of the brain. Exercise is a potent stimulator of NGF secretion. There are several natural compounds that stimulate nerve growth factor secretion. They include extracts from the mushroom, Hericium erinaceus. Although there are other edible mushrooms that are good for you, of the 4 edible mushrooms that were studied for their effect on NGF secretion, only Hericium erinaceus induced the secretion of NGF from human astrocytes in the Hippocampus of the brain. Another compound that stimulates the secretion of NGF is Acetyl-L-carnitine, aka ALCAR. Acetyl-L-carnitine also helps with neuropathic pain. In rodent models of Alzheimer’s disease, 150 mg/kg/day of ALCAR induced NGF secretion and increased choline acetyltransferase activity, which increasea acetylcholine levels in the hippocampus.
17. Provide the substrates for synaptic formation – uridine, choline, citocolin, DHA, EPA, and herring roe — The ability to form synaptic connections between neurons is a key part of forming memory. Several key molecules are needed to create these synapses and dendritic spines that are not made by the human body (e.g. DHA) or are made in inadequate amounts (e.g. citicoline). The omega-3 fatty acid called docosahexaenoic acid (DHA) is probably the “rate-limiting substrate” in the formation of presynaptic and postsynaptic proteins. DHA alone will increase the formation of synapses and increase cognitive performance in humans and experimental animals, but the addition of two other circulating precursors for phosphatidylcholine also enhance memory formation. These two other precursors are uridine (which gives rise to brain UTP and CTP) and choline (which gives rise to phosphocholine). Phosphatidylcholine (PC) is the major phosphatide found in human neuronal connections. The other two major synaptic ingredients are uridine and DHA. Studies have shown that the aministration of choline, uridine, and DHA together have a greater effect than the sum of the individual effects (i.e. they have a synergistic effect on generating synapses and dendritic spines). DHA alone increased the synthesis of hippocampal phospholipids by 8-75%, with the greatest percentage being in the synthesis if PC (phosphatidylcholine). There are still controversies as to how much DHA a person should take per day.
The MEND program recommends 320 mg of DHA/day, but other experts recommend as much as 2,000 mg/day of DHA. Herring roe, the eggs from the Herring forage fish, is another good source of n-3 polyunsaturated fatty acids that have a high phospholipid content. MOPL 30 is a supplement product made by Artic Nutrition that includes a lot of phospholipids and a 3:1 ratio of DHA:EPA. The MOPL 30 proprietary supplement not only increased neuronal generation, it also decreased plasma triacylglycerol and non-esterified fatty acids as well as increased HDL-cholesterol. Although fasting glucose did not change, the glucose measurement on OGTT decreased at 10 minutes and 120 minutes into the test. Instead of taking herring roe, uridine, or choline, the MEND program recommends citocoline (aka CDP-Choline) an intermediate compound in the generation of phosphatidylcholine from choline (i.e. already half made). It is marketed under many names worldwide, including Ceraxon, Cognizin, NeurAxon, Somazina, Synapsine, etc. Studies have shown that citocoline increases dopamine receptor densities, prevents memory impairment, improve focus and mental energy. Citocoline may also help treat attention deficit disorder (ADD). The MEND program recommends a dose of 500 mg of Citocoline twice a day, 320 mg of DHA per day, and 180 mg of EPA per day.
18. Optimize antioxidants – mixed tocopherols, tocotrienols, Selium, blueberries, NAC, Vit C, a-lipoic acid. Although the free radical theory of aging has largely been proven to be incorrect as the “cause of aging”, there is no question that the “effect of aging” includes free radical damage to proteins, lipids, and nucleic acids that make up a cell. To try to mitigate these “downstream effects” of aging, many believe that the judicious use of antioxidants still plays a useful role in treating neurodegeneration. In this blog we have questioned that viewpoint and have pointed out that “antioxidants” like those mentioned often have powerful epigenetic impacts that better explain their actions(ref)(ref).
19. Optimize Zn:fCu ratio – Alzheimer’s disease may be caused (in part) by copper toxicity — The fact that Alzheimer’s disease was rare prior to 1900, yet now being very common has led many experts to look for environmental “causes” of AD. One of the leading “suspects” in a long list of environmental risks for AD is inorganic copper, which comes from drinking water and supplement pills. There is clear evidence from human subjects that serum free copper is elevated with AD and that the level of free copper in the serum correlates with cognition and predicts cognition loss. Animal studies have replicated these findings and have shown that as little as 0.12 ppm of coper in distilled drinking water in cholesterol-fed rabbits greatly enhanced the formation of AD.
A 2nd feature of AD is that those affected also have Zinc deficiency. A small clinical trial published in 2014 showed that in patients over the age of 70, Zinc supplementation protected against cognitive loss and also reduced serum free copper levels in AD patients. For these reasons, it is unclear if the efficacy of Zinc therapy is on restoring normal Zn levels or if it is due to reducing Cu levels.
The following Table lists the remaining interventions in Dale Bredesen’s list. These are fairly clear and we will not expand on them here.
|20. Ensure nocturnal oxygenation||Exclude or treat sleep apnea|||
|21. Optimize mitochondrial function||CoQ or ubiquinol, α-lipoic acid, PQQ, NAC, ALCAR, Se, Zn, resveratrol, ascorbate, thiamine|||
|22. Increase focus||Pantothenic acid||Acetylcholine synthesis requirement|
|23. Increase SirT1 function||Resveratrol|||
|24. Exclude heavy metal toxicity||Evaluate Hg, Pb, Cd; chelate if indicated||CNS effects of heavy metals|
|25. MCT effects||Coconut oil or Axona|||
Neuroinflammation “causes” all of the neurodegeneratove diseases
Although we will save most of our discussion on the science of AD to the coming Part 2 blog entry in this series, we comment here a bit more on the the science behind most of the above interventions – their neuroinflammatory nature.
In all neurodegeneratiave diseases (both familial and sporadic cases), there is evidence of a chronic, low grade brain inflammation that does not go away. Histologically, this is called “gliosis”, a term that describes what is seen under the microscope. As mentioned above, microglial cells are increased in number and they appear “angry” (i.e. they are activated) likely due to the presence of Aβ1-42. It is likely that these microglial cells are secreting pro-inflammatory factors which are causing the inflammation, although the picture is actually much more complex. Vince has written about this in 2011 and before in the blog entries Key roles of glia and microglia in age-related neurodegenerative diseases, New views of Alzheimer’s disease and new approaches to treating it, and Alzheimer’s Disease Update. We surface some additional insights here and in Part 2..
This illustration portrays some of the inflammatory processes that go on when microglia and astrocytes are activated:
Image and legend source The 2014 publication Inflammasomes in neuroinflammation and changes in brain function: a focused review “Cytokines hypothesis of neuroinflammation: Implications in comorbidity of systemic illnesses with psychiatric disorders. Pro-inflammatory cytokines can migrate between systemic circulation and brain in both directions which could explain the comorbidity of systemic illnesses with psychiatric disorders. There are three pathways for the transport of pro-inflammatory cytokines from systemic circulation to brain as described by Capuron and Miller (2011): Cellular, Humoral, and Neural. Moreover, PAMPs and DAMPs from trauma, infection, and metabolic waste can prime glial cells to express pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. When expressed, these cytokines activates granulocytes, monocytes/macrophages, Natural Killer, and T cells and together contribute to the pathophysiology of neuroinflammation. Chronic neuroinflammation could result in neurodegeneration and associated psychiatric disorders. These pro-inflammatory cytokines also stimulate production and expression of anti-inflammatory cytokine by glial cells that function as negative feedback to reduce the expression of pro-inflammatory cytokines, subsiding the neuroinflammation. MCP-1, Monocyte chemoattractant protein-1; CP, Choroid plexus; CVO, Circumventricular organ.”
The chronic inflammation viewpoint of Alzheimer’s disease is related to but somewhat different than the Beta Amloid viewpoint, the viewpoint covered in my recent blog entry The Amyloid Beta face of Alzheimer’s Disease.
The situation is described in a 2014 publication by Landry and Liu-Ambrose: “An alternative to the classic amyloid centric view of AD suggests that late-onset AD results from age-related alterations in innate immunity and chronic systemic inflammation (for review see Krstic and Knuesel, 2013).
In the Part 2 blog entry we will go into the neuroinflammation hypothesis in further depth and will explore other theories as to causes of AD and the other neurodegenerative diseases.
So, a basic strategy for preventing or delaying the onset of neurodegenerative diseases is to mount a multifront war on systematic inflammation. The 25 Bredesen interventions described above are initiatives in that war.
Alzheimer’s disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer’s disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published . The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer’s disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.
Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP | Journal of Cell ScienceAuthor: SupremePundit
Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.
Determining how organisms obtain energy from the environment is fundamental to our understanding of life. In nearly all organisms, energy is stored and transported as adenosine-5′-triphosphate (ATP). In animals, the vast majority of ATP is synthesized in the mitochondria through respiration, a catabolic process. However, plants have co-evolved endosymbiotically to produce chloroplasts, which synthesize light-absorbing chlorophyll molecules that can capture light to use as energy for ATP synthesis. Many animals consume this light-absorbing chlorophyll through their diet. Inside the body, chlorophyll is converted into a variety of metabolites (Ferruzzi and Blakeslee, 2007; Ma and Dolphin, 1999) that retain the ability to absorb light in the visible spectrum at wavelengths that can penetrate into animal tissues. We sought to elucidate the consequences of light absorption by these potential dietary metabolites. We show that dietary metabolites of chlorophyll can enter the circulation, are present in tissues, and can be enriched in the mitochondria. When incubated with a light-capturing metabolite of chlorophyll, isolated mammalian mitochondria and animal-derived tissues, have higher concentrations of ATP when exposed to light, compared with animal tissues not mixed with the metabolite. We demonstrate that the same metabolite increases ATP concentrations, and extends the median life span of Caenorhabditis elegans, upon light exposure; supporting the hypothesis that photonic energy capture through dietary-derived metabolites may be an important means of energy regulation in animals. The presented data are consistent with the hypothesis that metabolites of dietary chlorophyll modulate mitochondrial ATP stores by catalyzing the reduction of coenzyme Q. These findings have implications for our understanding of aging, normal cell function and life on earth.
Light-driven ATP synthesis in isolated mammalian mitochondria
To demonstrate that dietary chlorophyll metabolites can modulate ATP levels, we examined the effects of the chlorophyll metabolite pyropheophorbide-a (P-a) on ATP synthesis in isolated mouse liver mitochondria in the presence of red light (λmax = 670 nm), which chlorin-type molecules such as P-a strongly absorb (Aronoff, 1950), and to which biological tissues are relatively transparent. We used P-a because it is an early metabolite of chlorophyll, however, most known metabolites of chlorophyll can be synthesized from P-a by reactions that normally take place in animal cells. Control samples of mitochondria without P-a, and/or kept in the dark were also assayed. In the presence of P-a, mitochondria exposed to red light produce more ATP than mitochondria without P-a (Fig. 1A) or mitochondria kept in the dark (supplementary material Fig. S1A–D). Mitochondrial membrane potential (Fig. 1B) and oxygen consumption (Fig. 1C) increased upon increased light exposure in P-a-treated mitochondria. Light or P-a alone had no effect on any of the above measures of mitochondrial activity (supplementary material Fig. S1E–G). With too much added P-a, ATP concentrations and the rate of oxygen consumption started to return to the levels in mitochondria not incubated with P-a (supplementary material Fig. S1G). Addition of the electron transport inhibitor, sodium azide, reduced the light- and P-a-fueled oxygen consumption by 57% (supplementary material Fig. S1H–I), consistent with oxygen consumption occurring through the electron transport system. Observations were consistent with enhanced ATP production driven by oxidative phosphorylation.
To determine whether P-a associates with mitochondria, we measured P-a fluorescence at 675 nm in the presence of increasing amounts of heart mitochondrial fragments obtained from sheep (Fig. 2A,B). After increasing the concentration of mitochondria, P-a fluorescence increased abruptly, by fivefold, and quickly reached a plateau (Fig. 2B). The abrupt change in fluorescence reflects a change in the environment of P-a, consistent with its change from an aqueous environment to one in which it is presumably associated with a protein. This threshold-sensitive behavior is consistent with zero-order ultrasensitivity, or positively cooperative binding, as described by Goldbeter and Koshland, and suggests a coordinated interaction between the metabolite and mitochondrial fragments (Goldbeter and Koshland, 1981). In contrast, this threshold sensitivity was not observed when increasing amounts of bovine serum albumin (BSA) were added to a solution of P-a; instead, fluorescence steadily increased (supplementary material Fig. S1J).
Catabolic reduction of coenzyme Q10 (CoQ10) is a rate limiting step in respiration (Crane, 2001). The majority of CoQ10 molecules exist in two alternate states of oxidation: ubiquinone, the oxidized form, and ubiquinol, the reduced form. To show that the P-a metabolite could catalyze the photoreduction of mitochondrial CoQ10, we measured the oxidation state of CoQ10 in the above sheep heart mitochondrial fragments in response to exposure to red light. We exposed the mitochondria to light for 10 minutes and measured the percentage of reduced and oxidized CoQ10 by high performance liquid chromatography (HPLC) (Qu et al., 2013). In the freshly isolated mitochondria fragments, nearly all the CoQ10 was oxidized in the form of ubiquinone. However, when we incubated the mitochondria with P-a and exposed the suspension to light, 46% of CoQ10 was reduced (Table 1, entry 1). In comparison, as a positive control, we energized the mitochondria with glutamate/malate and kept the suspension in the dark, yielding a 75% reduction of CoQ10 within 10 minutes (entry 2). In the absence of light, no reduction occurred (entry 3). Upon denaturing the mitochondrial proteins with heat, no reduction occurred (entry 4). Likewise, there was a lack of CoQ10 reduction with CoQ10, P-a and light in the absence of mitochondria (entry 5). These observations are consistent with the fluorescence data in Fig. 2A,B, showing that mitochondrial proteins sequester and organize P-a. In the absence of added P-a, a 2–14% reduction was observed, depending on the mitochondrial preparation used (entry 6). We attribute this ‘background reduction’ to the actions of endogenous chlorophyll metabolites, which we were able to detect by fluorescence spectroscopy (see Distribution of light-absorbing dietary chlorophyll, below).
Light-driven ATP synthesis in rodent tissue homogenates
To determine whether chlorophyll metabolites and light could influence ATP production in whole tissues, we treated mouse brain homogenates with P-a and exposed them to 670-nm light. The treated brain homogenates synthesized ATP at a 35% faster rate than a control homogenate that was not incubated with P-a [relative ATP synthesis rates (means with standard error and 95% confidence intervals (CI) were: treated, 171.7±8.1 (CI: 154.6–188.7); control, 111.3±9.1 (CI: 92.5–130.0); Fig. 3A]. No linear correlation between the increase in ATP concentrations and the amount of added P-a was observed. Increasing concentrations of P-a elicited the same increase in ATP (supplementary material Fig. S2A,B).
To demonstrate that photon absorption by P-a was necessary to enhance ATP production, we exposed the P-a-treated brain homogenates to greenish (500 nm) and red (630, 670 and 690 nm) light, all with the same total energy. Wavelengths of light that were more strongly absorbed by P-a produced the largest increase in ATP. For example, the ATP concentration increased by ∼16-fold during exposure to 670 nm light; relative to the same sample kept in the dark, it increased by two-to-fivefold during exposure to 500, 630 and 690-nm light of equal energy (Fig. 3B).
In addition to brain homogenates, P-a also enhanced ATP production in adipose, lens and heart homogenates (supplementary material Fig. S2C–E). Quantification of ATP by both the luciferase assay and high-performance liquid chromatography (HPLC) gave similar results (supplementary material Fig. S2E–F).
Distribution of light-absorbing dietary chlorophyll
Chlorophylls and its metabolites, both chlorins, have signature absorption and admission spectra (Aronoff, 1950). Namely they absorb strongly (ε≈50,000 M−1 cm−1) at ∼665–670 nm and demonstrate intense fluorescence emissions at ∼675 nm, which differentiate chlorins from endogenous molecules in mammals (Aronoff, 1950). To examine whether dietary chlorophyll and/or its metabolites were present in animal tissue after oral consumption, we fed mice a chlorophyll-rich diet. Brain (Fig. 4A) and fat (Fig. 4C) extracts from these mice exhibited red fluorescence at 675 nm when excited with a 410-nm light [brain: treated, 15.4±6.7 (n = 6); control: 4.2±2.6 (n = 6; means ± s.d.); P<0.01]. The excitation spectrum of this 675-nm peak (Fig. 4B) was similar to that of known chlorophyll metabolites with an intact chlorin ring: with maxima at 408, 504, 535, 562 and 607 nm. This red fluorescence diminished, as measured by the area under the 675 nm peak, when animals were given a chlorophyll-free diet for 2 weeks. Red fluorescence could also be seen using fluorescence imaging; fluorescence was stronger in the bodies and brains of animals fed chlorophyll than in animals given a chlorophyll-poor diet [Fig. 4D; mean gray value in the boxed areas with standard deviation and minimum and maximum gray value shown in brackets were: treated brain, 118 (97–138); control brain, 82 (60–100); treated back fat pad, 116 (97–132) and control back fat pad, 35 (25–46)]. The red fluorescence was enriched in the gut and intestines, consistent with dietary chlorophyll being the source of the fluorescence.
To determine whether the red fluorescence was localized to mitochondria, we measured the relative 675-nm fluorescence in whole liver homogenates and mitochondria isolated from these homogenates. As measured by fluorescence intensity, isolated mitochondria contained 2.3-fold as much of the 675-nm fluorescent metabolite(s) per milligram of protein as did the whole liver homogenate. This observation suggests that P-a was concentrated in the mitochondria, consistent with data summarized in Fig. 2A,B, and literature reports (MacDonald et al., 1999; Tang et al., 2006).
Fat and plasma extracts from rats fed chlorophyll-rich diets were further analyzed by HPLC to elucidate the source of the red 675-nm fluorescence. Fig. 5A shows a representative chromatogram with compounds in the eluting solvent that displayed 675-nm fluorescence when excited with 410-nm light. Rat fat extracts and plasma extracts both contained similar chlorophyll-derived metabolites (similar chromatograms not illustrated). Two groups of compounds eluting at 23–30 minutes and 40–46 minutes were detected. Compounds eluting between 23 and 30 minutes had similar retention times to those of the chlorophyll metabolites without the phytyl tail, with at least one carboxylate group, such as P-a. The absorption spectra (the locations of the absorbance maxima and the Soret-to-Qy-band ratios) of this group of compounds were consistent with demetalated chlorophylls (Rabinowitch, 1944), as shown in Fig. 5B. In addition, the spectra of this group of peaks were indicative of coordination to a metal ion. A representative spectrum of such a presumably metalated metabolite is shown in Fig. 5C, showing a red shifted Soret band, a blue shifted Qy-band and a Soret-to-Qy-band ratio of ∼1. The compounds eluting between 40 and 46 minutes had similar retention times to that of the demetalated chlorophyll-a standard (pheophytin-a). In addition, these compounds partitioned with hexanes (polarity index = 0.1) when mixed with hexanes and acetonitrile (polarity index = 5.8). This latter characteristic is consistent with a lack of a carboxylic acid group, or an esterified P-a, such as pheophytin-a. Similar HPLC chromatograms from fat extracts of swine fed chlorophyll rich diets (Mihai et al., 2013) were recorded (supplementary material Fig. S2G), suggesting that uptake and distribution of chlorophyll metabolites were not unique to mice and rats.
We quantified total blood pigments from rats that absorbed at 665 nm. Using an extinction coefficient of 52,000 at 665 nm (Lichtenthaler, 1987), which is typical of chlorophyll-a-derived pheophytins, we estimated a plasma concentration of 0.05 µM in two rats fed a chlorophyll-rich diet. The 665-nm peak was absent in animals fed a chlorophyll-poor diet. The amount of measured total metabolite was five- and two-times higher than that reported for the fat soluble vitamins K (Tovar et al., 2006) and D (Halloran and DeLuca, 1979), respectively, in the rat.
Light-driven ATP synthesis in C. elegans
Next, we used C. elegans to evaluate the effects of light-stimulated ATP production in a complex organism. As C. elegans age, there is a drop in cellular ATP (Braeckman et al., 1999; Braeckman et al., 2002). We hypothesized that the worm would live longer if it could offset this decline in ATP by harvesting light energy for ATP synthesis. As our model system, we used firefly luciferase-expressing C. elegans, which upon incubation with luciferin emit a luminescence that is proportional to their ATP pools (Lagido et al., 2009; Lagido et al., 2008; Lagido et al., 2001). Upon incubation with P-a, worms incorporated the metabolite, as measured by fluorescence spectroscopy (supplementary material Fig. S3A). To determine whether there were changes in ATP stores in response to light, we plated two groups of worms into 96-well plates containing luciferin substrate. We measured worm luminescence at time zero. We then exposed one group to 660-nm light and kept the other in the dark and periodically measured luminescence in both groups of worms (summarized in Fig. 6A,B). To determine whether ATP increased in light-exposed animals, we subtracted the luminescence signal of the worms kept in the dark from that of the worms exposed to light (Fig. 6C). Worms that were given P-a had a statistically significant increase in ATP when exposed to light, whereas control worms showed no increase. The metabolite alone had no effect on ATP levels when the worms were kept in the dark (i.e. luminescence intensity remained constant throughout the experiment). The elevated luminescence signal persisted for 1 hour after the light was turned off, at which time measurement ceased. However, the luminescence intensity did not further increase during the time the light was off. It was unclear whether this persistent signal reflected the kinetics of the luciferase–luciferin reaction, luciferase expression, or actual ATP pools. Thus ATP was quantified by additional methods.
As an alternative means of determining whether light stimulated ATP synthesis, we plated luciferase-expressing worms into a 96-well plate without the luciferin substrate, and exposed them to light. ATP status was determined at time zero, immediately before light exposure, and at 15-minute intervals for a total of 45 minutes by adding the luciferin substrate to a group of worms and measuring luminescence (Fig. 6D,E). We found an increase in ATP when 5-day-old and 10-day-old adult worms were fed the metabolite and exposed to light.
We further confirmed the in vivo increase in ATP using two additional ex vivo methods. After light treatment, we lysed the worms, extracted their ATP and quantified ATP in the homogenate using either the firefly luciferase assay or HPLC (supplementary material Fig. S3B,C). Both methods were consistent with the in vivo ATP measurements.
In addition to an increase in ATP, worms treated with P-a exhibited a 13% increase in respiration when exposed to light, as measured by oxygen consumption. However, light had no effect on the respiration rates in untreated worms (supplementary material Fig. S3D). This observation is consistent with an increase in ATP through oxidative phosphorylation, in accordance with the mitochondrial data. Despite the increase in ATP, the levels of reactive oxygen species (ROS) were equivalent in treated and untreated worms during 5 hous of light exposure, as measured using 2′,7′-dichlorofluorescin diacetate (supplementary material Fig. S3E). In fact, although the difference was not statistically significant, treated worms exhibited, on average, lower levels of ROS.
Light harvesting to extend life span
We next tested whether photonic energy absorption by P-a could prolong life. Life span measurements were taken in liquid cultures according to the method of Gandhi et al. and Mitchell et al. (Gandhi et al., 1980; Mitchell et al., 1979). Adult worms were incubated with P-a for 24 hours. Beginning at day 5 of adulthood, we exposed the worms to red light in a daily 5 hours:19 hours light∶dark cycle. Control worms were not given P-a or exposed to light, but otherwise were kept under identical conditions. Counts were made at 2- to 3-day intervals and deaths were assumed to have occurred at the midpoint of the interval. To obtain the half-life, we plotted the fraction alive at each count verses time and fitted the data to a two-parameter logistic function, known to accurately fit survival of 95% of the population (Vanfleteren et al., 1998). The group treated with P-a and light had a 17% longer median life span than the group that was not treated with P-a, but exposed to light (Fig. 7A,B). P-a treatment alone, in the absence of light, had no effect on life span (supplementary material Fig. S4B). Light treatment alone decreased life span by 10% (supplementary material Fig. S4B), in accordance with reports that nematodes survive better in complete darkness (Thomas, 1965). This decrease in median life span brought on by light was reversed when the worms were treated with P-a. The increased median life span with light and P-a was reproducible with different batches of worms (supplementary material Fig. S4B–E). Increasing the amount of P-a past a certain threshold, however, lead to a gradual decrease in lifespan approaching that of animals not treated with P-a (supplementary material Fig. S4B,C).
We also examined life span longitudinally. We placed 6-day-old adult P-a- and non-P-a-treated worms into a 96-well plate, exposed them to red light for 5 hours per day and compared the percentage dead and alive after 15 days. Result: 47% of the P-a-treated worms were alive (175 alive; 200 dead) after 15 days, versus 41% of the control worms (111 alive; 163 dead), consistent with the cross-sectional experiments above.
Photoreduction of coenzyme Q
Upon incubation of: (1) isolated mouse mitochondria; (2) mouse brain, heart and lens homogenates; (3) homogenized duck fat; and (4) live C. elegans, with a representative metabolite of chlorophyll, light exposure was able to increased ATP concentrations. These observations in a variety of animal tissues perhaps demonstrate the generality of this phenomenon. To synthesize ATP, mitochondrial NADH reductase (complex I) and succinate reductase (complex II) extract electrons from NADH and succinate, respectively. These electrons are used to reduce mitochondrial CoQ10, resulting in ubiquinol (the reduced form of CoQ10). Ubiquinol shuttles the electrons to cytochrome c reductase (complex III), which uses the electrons to reduce cytochrome c, which shuttles the electrons to cytochrome c oxidase (complex IV), which ultimately donates the electrons to molecular oxygen. As a result of this electron flow, protons are pumped from the mitochondrial matrix into the inner membrane space, generating a trans-membrane potential used to drive the enzyme ATP-synthase.
The ‘pool equation’ of Kröger and Klingenberg describes the total rate of electron transfer: Vobs = VoxVred/(Vox+Vred), where Vred is ubiquinone reduction and Vox is ubiquinol oxidation (Kröger and Klingenberg, 1973). Based on this equation, the major roles of complexes I and II can be considered to maintain the mitochondrial ubiquinol pool, and to reduce ubiquinone, which should result in increased ATP synthesis. We reasoned the reduction of CoQ10 could be a potential step in the respiratory pathway in which chlorophyll metabolites could influence ATP levels, as it is known that chlorophyll-type molecules can photoreduce quinones (Chesnokov et al., 2002; Okayama et al., 1967). Indeed, a primary step during photosynthesis is the reduction of the quinone, plastoquinone, by a photochemically excited chlorophyll a (Witt et al., 1963). We hypothesized that if the reduction of mitochondrial ubiquinone could be catalyzed by a photoactivated chlorophyll metabolite, such as P-a, then ATP synthesis would be driven by light in mitochondria with these dietary metabolites. In the proposed mechanism, electrons would be transferred by a metabolite of chlorophyll to CoQ10, from a chemical oxidant present in the mitochondrial milieu. Many molecules, such as dienols, sulfhydryl compounds, ferrous compounds, NADH, NADPH and ascorbic acid, could all potentially act as electron donors. Throughout mammalian evolution, photons of red light from sunlight have been present deep inside almost every tissue in the body. Photosensitized electron transfer from excited chlorophyll-type molecules is widely hypothesized to be a primitive form of light-to-energy conversion that evolved into photosynthesis (Krasnovsky, 1976). Thus it is tempting to speculate that mammals possess conserved mechanisms to harness photonic energy.
Photoexcitation of chlorophyll and derivatives produces the excited singlet state (*1). Oxidative quenching of this singlet state by ubiquinone is possible. Electron transfer could take place through proteins or in solution. Escape from the charge transfer complex and protonation would yield ubisemiquinone, which accounts for 2–3% of the total ubiquinone content of mitochondria (De Jong and Albracht, 1994). Ubisemiquinone can be reduced to ubiquinol by repeating the above sequence or by disproportionation to give one molecule of ubiquinol and one molecule of ubiquinone. Back-electron transfer, from the photoreduced metabolite to the oxidized quinone, could be inhibited by disproportionation or by organizing the chlorophyll derivative and ubiquinol through protein binding. In line with the CoQ10 photoreduction hypothesis, we observed mitochondrial CoQ10 was reduced when isolated mitochondria were exposed to light and P-a (Table 1). Also consistent with light and/or P-a acting upstream of complexes I and II, in isolated mitochondria we observed an increase in ATP in the absence of added electron transport substrates, such as glutamate and malate (Fig. 1A; supplementary material Fig. S1A–C). However, further evidence is needed to confirm this mechanistic hypothesis.
The effect of light in vivo
Intense red light between 600 and 700 nm has been reported to modulate biological processes (Hashmi et al., 2010; Passarella et al., 1984; Wong-Riley et al., 2005), and has been investigated as a clinical intervention to treat a variety of conditions (Hashmi et al., 2010). Exposure to red light is thought to stimulate cellular energy metabolism and/or energy production by, as yet, poorly defined mechanisms (Hashmi et al., 2010). In the presence of P-a, we observed changes in energetics in animal-derived tissues initiated with light of intensity and wavelengths (≈670 nm at ≈0.8±0.2 W/m2) that can be found in vivo when outdoors on a clear day. On a clear day the amount of light illuminating your brain would allow you to comfortably read a printed book (Benaron et al., 1997). In humans, the temporal bone of the skull and the scalp attenuate only 50% of light at a wavelength of ∼670 nm (Eichler et al., 1977; Wan et al., 1981). In small animals, light can readily reach the entire brain under normal illumination (Berry and Harman, 1956; Massopust and Daigle, 1961; Menaker et al., 1970; Vanbrunt et al., 1964). Sun or room light over the range of 600–700 nm can penetrate an approximately 4-cm-thick abdominal wall with only three-to-five orders of magnitude attenuation (Bearden et al., 2001; Wan et al., 1981). Photons between 630 and 800 nm can penetrate 25 cm through tissue and muscle of the calf (Chance et al., 1988). Adipose tissue is bathed in wavelengths of light that would excite chlorophyll metabolites (Bachem and Reed, 1931; Barun et al., 2007; Zourabian et al., 2000). Thus, identification of pathways, which might have developed to take advantage of this photonic energy, may have far-reaching implications.
Dietary chlorophyll in animals
A potential pathway for photonic energy capture is absorption by dietary-derived plant pigments. Little is known about the pharmacokinetics and pharmacodynamics of dietary chlorophyll or its chlorin-type metabolites in human tissues. Here, we observed the accumulation of chlorin-type molecules in mice, rats and swine administered a diet rich in plant chlorophylls (Figs 4, 5; supplementary material Fig. S2G). Data suggests that sequestration from the diets of chlorophyll-derived molecules, which are capable of absorbing ambient photonic energy, might be a general phenomenon.
To date, the reported chlorophyll metabolites isolated from animals have been demetalated (Egner et al., 2000; Fernandes et al., 2007; Scheie and Flaoyen, 2003). The acidic environment of the stomach is thought to bring about loss of magnesium from the chlorophyll (Ferruzzi and Blakeslee, 2007; Ma and Dolphin, 1999). Our absorbance data from extracted pigments from rat fat is consistent with the presence of chlorophyll metabolites bonded to a metal (Fig. 5). If true, the presence of a metal derivative in fat tissue suggests that the pigment was actively re-metalated to take part in coordination chemistry. The identification of several metabolites in the fat and plasma of rats and swine fed a chlorophyll-rich diet that are similar to ones found in plants is significant. However, the structures of the metabolites remain to be elucidated. Chlorin-type molecules are similar in structure and photophysical properties and thus can carry out similar photochemistry (Gradyushko et al., 1970). Our data demonstrate that dietary metabolites of chlorophyll can be distributed throughout the body where photon absorption may lead to an increase in ATP as demonstrated for the chlorin P-a. Indeed, P-a could have been transformed into other metabolites, as most known metabolites of chlorophyll can be formed from P-a by reactions that normally take place in animal cells.
There relationship between the increase in ATP and the amount of added P-a was not linear (supplementary material Fig. S2A,B). ATP stimulation by light in the presence of P-a better fitted a binary on/off, rather than a graded response to P-a. Increasing concentrations of P-a elicited the same increase in ATP, after light exposure. However, with too much added P-a, ATP levels began to fall. This on/off response was also consistent with the observed cooperative binding mode of P-a with mitochondria fragments, suggesting that the threshold response may be regulated by mitochondrial binding of P-a. If chlorophyll metabolites are found to be involved in energy homeostasis, a better understanding of their pharmacodynamics and pharmacokinetics will be needed.
ATP stores and life span
Light of 670 nm wavelength that penetrates the human body, yields ∼43 kcal/mol (1.18×10−22 kcal/photon). Given estimated concentrations of chlorophyll derivatives in the body (Egner et al., 2000; Fernandes et al., 2007; Scheie and Flaoyen, 2003) and the photon flux at 670 nm (Bachem and Reed, 1931; Barun et al., 2007; Bearden et al., 2001; Benaron et al., 1997; Chance et al., 1988; Eichler et al., 1977; Menaker et al., 1970; Vanbrunt et al., 1964; Wan et al., 1981; Zourabian et al., 2000), each chlorophyll metabolite would be expected to absorb only a few photons per second. As such, one might anticipate negligible amounts of additional energy. Organization of chlorophyll metabolites into supramolecular structures, similar to chlorophyll antenna systems in photosynthetic organisms, would increase the effective cross-sectional area of photon absorption and, thus, photon catch. Indeed, our observed positively cooperative binding with mitochondrial fragments is evidence for such organization. Even so, to approach the rate of ATP synthesis powered by NADH or FADH2, sufficient P-a pigment would have to be added to turn animals green. Nevertheless, in model systems, we measure an increase in ATP upon light absorption and changes in fundamental biology (extention in life span). Regardless of the mechanism by which ATP is increased or the measured amount of the increase, perhaps the larger question is: how much of an increase in ATP is enough to make a biological difference?
In animals, treatment with P-a and light both increased ATP and median life span, suggesting that light in the presence of these light absorbing dietary metabolites can significantly affect fundamental biological processes. We previously observed that chlorophyll metabolites enabled photonic energy capture to enhance vision using a mouse model (Isayama et al., 2006; Washington et al., 2004; Washington et al., 2007). Because ATP can regulate a broad range of biological processes, we suspect that ATP modulation also played a role in vision enhancement. The increase in life span may seem contradictory, given that there are studies suggesting that limiting metabolism and ATP synthesis increases the life span of C. elegans. It has been proposed that the life span of this worm might be determined by the metabolic status during development (Dillin et al., 2002) and that there might be a coupling of a slow early metabolism and longevity (Lee et al., 2003). Other observations have led to the hypothesis that increased life span may be achieved by decreasing total energy expenditure across the worm’s entire life span (Van Raamsdonk et al., 2010). However, most studies decrease ATP synthesis from hatching through genetic engineering. By contrast, here, we were able to increase ATP during adulthood at a time when ATP stores reportedly begin to decline. For example, by day 4 of adulthood, the level of ATP and oxygen consumption can drop by as much as 50% compared to day zero (Braeckman et al., 1999; Braeckman et al., 2002). This difference in timing might account for why we observed an increase in life span in response to an increase in ATP. We note that besides caloric restriction, there are only a few interventions that are known (Petrascheck et al., 2007) to increase life span when given to an adult animal.
Alternative mechanisms of life-span extension cannot be ruled out. For example, an increase in reactive oxygen species (ROS) is thought to increase life span in C. elegans (Heidler et al., 2010; Schulz et al., 2007). Upon photon absorption, metabolites of chlorophyll can transfer energy to oxygen, resulting in the generation of singlet oxygen, a ROS. Thus life-span extension seen here might be a result of an increase in ROS due to the generation of singlet oxygen. However, our published data with blood plasma (Qu et al., 2013) and data here from C. elegans do not show an increase in ROS. As ubiquinol is a potent lipid antioxidant (Frei et al., 1990) any ROS increase might be offset by an increase in ubiquinol, generated from the photoreduction of coenzyme Q. Indeed, by producing ubiquinol, P-a might have increased life span by an alternative method by protecting against long-term oxidative damage, which is also a mechanism that has been shown to increase C. elegans life span (Ishii et al., 2004). Further research will be needed to distinguish between the above possible mechanisms.
Both increased sun exposure (Dhar and Lambert, 2013; John et al., 2004; Kent et al., 2013a; Kent et al., 2013b; Levandovski et al., 2013) and the consumption of green vegetables (Block et al., 1992; Ferruzzi and Blakeslee, 2007; van’t Veer et al., 2000) are correlated with better overall health outcomes in a variety of diseases of aging. These benefits are commonly attributed to an increase in vitamin D from sunlight exposure and consumption of antioxidants from green vegetables. Our work suggests these explanations might be incomplete. Sunlight is the most abundant energy source on this planet. Throughout mammalian evolution, the internal organs of most animals, including humans, have been bathed in photonic energy from the sun. Do animals have metabolic pathways that enable them to take greater advantage of this abundant energy source? The demonstration that: (1) light-sensitive chlorophyll-type molecules are sequestered into animal tissues; (2) in the presence of the chlorophyll metabolite P-a, there is an increase in ATP in isolated animal mitochondria, tissue homogenates and in C. elegans, upon exposure to light of wavelengths absorbed by P-a; and (3) in the presence of P-a, light alters fundamental biology resulting in up to a 17% extension of life span in C. elegans suggests that, similarly to plants and photosynthetic organisms, animals also possess metabolic pathways to derive energy directly from sunlight. Additional studies should confirm these conclusions.
MATERIALS AND METHODS
Two light sources were used for all experiments, either a 300 W halogen lamp equipped with a variable transformer and band pass interference filters [500, 632, 670, 690 nm with full-width half maximum (FWHM) of 10 nm] or a 1.70 W, 660 nm, LED light bulb. Luminous power density was set to 0.8±0.2 W/m2 as measured by a LI-250A light meter (LI-COR Biosciences, Lincoln, NE). The intensity of red light used was 30–60 times less than the level of red light that we measured on a clear March afternoon in New York City and is less than the level that several organs are exposed to in vivo. Pyropheophorbide-a (P-a, 95% purity) was obtained from Frontier Scientific, Logan, UT. For all experiments, prior to exposing samples to light, we minimized light exposure by preparing samples/experiments with laboratory lights turned off, using a minimum amount of indirect sunlight that shone through laboratory windows (>0.001 W/m2).
Animal protocols were approved by the Institutional Animal Care and Use Committee of Columbia University. Mice (ICR, Charles River, Wilmington, MA) weighing 22–28 g and rats (Fisher 344, Harlan Teklad, Indianapolis, IN), weighing 300 g were used. Swine, fed a chlorophyll-rich diet have been described previously (Mihai et al., 2013).
Continuous ATP monitoring in isolated mouse liver mitochondria
Mice were fed a chlorophyll-poor, purified rodent diet supplied by Harlan (Indianapolis, IN) for a minimum of 2 weeks. We isolated mouse liver mitochondria by differential centrifugation according to existing procedures (Frezza et al., 2007) and used only preparations with a minimum respiratory control ratio above 4.0 [state III/II, using glutamate (5 mM final) and malate (2.5 mM final) as measured with an oxygen electrode from Qubit Systems Inc., Kingston, ON, Canada]. Mitochondria at a final concentration of ≈1 mg protein/ml as determined by the Coomassie Plus (Bradford) protein assay (Thermo Fisher Scientific, Rockford, IL) in buffer A (0.250 M mannitol, 0.02 M HEPES, 0.01 M KCl, 0.003 M KH2PO4, 0.0015 M MgAc2·H2O, 0.001 M EGTA, 1 mg/ml fatty acid–poor BSA, pH 7.4) were incubated with P-a for 30 minutes at 0°C. ADP was added (0.5 mM final concentration) and then 250 µl aliquots of this suspension were placed in nine wells of a 96-well plate for exposure to light at room temperature. At various times, 20 µl aliquots were withdrawn, added to 150 µl lysis buffer (10 mM Tris, pH 7.5; 100 mM NaCl; 1 mM EDTA and 1% Triton X-100), and ATP levels were determined with a commercial kit (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. Controls were treated in the same way, except they were: (1) incubated at 0°C without P-a (shown), (2) not exposed to light and (3) were incubated without P-a and not exposed to light.
Membrane potential measurement
Mitochondrial membrane potential was monitored in buffer A as described by Feldkamp et al. (Feldkamp et al., 2005). Measurements were made in a 3 ml cuvette placed inside a fluorescence spectrometer (Fluorormax-4, HORIBA Jobin Yvon, Horiba Scientific, Kyoto, Japan) with a final reaction volume of 1 ml. For light exposure, we used a fiber optic light guide to capture and direct light from a 660 nm LED light bulb into the spectrometer. The end of the fiber optic cable was positioned 1 cm above the reaction mixture. Prior to these experiments, light power was measured 1 cm from the end of the fiber optic cable.
Oxygen consumption measurement
Mitochondrial oxygen consumption was measured using an oxygen electrode cuvette (OX1LP-1 ml; Qubit Systems Inc., Kingston, ON, Canada) according to the manufacturer’s instructions. Reactions were run with mitochondria at a concentration of ≈1 mg protein/m’ in buffer A. For light exposure, a 660-nm LED was directed at the plastic [poly-(methyl methacrylate)] chamber.
For inhibition of respiration, sodium azide was added at a final concentration of 0.005 M from a stock solution in water. Sodium azide inhibits cytochrome oxidase (complex IV): oxygen consumption during state 3 respiration is progressively inhibited by increasing concentrations of azide (Bogucka and Wojtczak, 1966).
Analysis of zero-order ultrasensitivity
Mitochondria from sheep hearts were prepared as previously described (Smith, 1967) on two separate occasions from 2 and 1 sheep heart(s) using ‘Procedure 1’. We used mitochondrial fragments to allow P-a direct access to the respiratory chain, to minimize potential complications due to variable rates of P-a import. Mitochondrial isolation started within 1 hour of the death of the animal and the hearts were transported to the laboratory in a bath of 0.25 M sucrose, 0.1 M tris(hydroxymethyl)aminomethane (Tris) at pH 7.5, which was surrounded by ice. Mitochondria were isolated and stored in 250 µl aliquots at a concentration of ∼60 mg of protein/ml in 300 mM trehalose, 10 mM HEPES–KOH pH 7.7, 10 mM KCl, 1 mM EGTA, 1 mM EDTA and 0.1% BSA at −80°C (Yamaguchi et al., 2007) until use. The thawed mitochondria exhibited a respiratory control ratio of ∼1, indicating mitochondrial fragmentation.
Analysis of coenzyme Q redox status
We used sheep heart mitochondria because they contain relatively large amounts of CoQ10, which expedited analysis. For evaluation of CoQ10 redox ratios, frozen mitochondria were thawed at 37°C and diluted with 500 µl buffer A to create a mitochondrial stock solution, which was kept on ice until use. For reactions, 50 µl of this stock suspension was added to 500 µl of buffer A, containing 0.5 µg/ml antimycin A from a 25 µg/ml stock solution in ethanol. Antimycin A binds to the Qi site of cytochrome c reductase (complex III), thereby inhibiting the upstream oxidation of any produced ubiquinol. Pa was added (25 µM final concentration) from a 1.3 mg/ml stock solution in DMSO. The suspension was added to a test tube, mixtures purged with argon and the reactions initiated by placing the tube between two LED light bulbs (previously described). We irradiated the samples for 10 minutes at room temperature. For negative controls, we repeated the above sequence changing the following: (1) in the absence of light; (2) in the absence of added P-a; (3) with heat denatured mitochondria; and (4) in the absence of added mitochondria but with added coenzyme Q. For a positive control we added 10 µl of a stock solution of 0.25 M glutamate/0.125 M malate in Tris buffer at pH 7. For mitochondrial denaturing, 200 µl of stock mitochondrial suspension was purged with argon and placed in a bath at 70°C for 5 minutes. For control reactions without added mitochondria, a coenzyme Q stock solution in buffer A was prepared by adding ALL-QTM (DSM Nutritinal products, Switzerland), a water-soluble coenzyme Q solution containing 10% coenzyme Q, modified food starch, sucrose and medium chain triglycerides, to buffer A. For these reactions 50 µl of the water-soluble Coenzyme Q stock or the denatured suspension was used as above in place of the mitochondrial stock solution. All reactions were adjusted to give the same amount of coenzyme Q in the reaction mixture as measured by HPLC.
To quantify relative ubiquinone and ubiquinol concentrations, a 50 µl aliquot was taken from the reaction mixture and was added to 200 µl of 0.4 M perchloric acid and 100 µl isopropyl ether containing 1 mg of butylated hydroxytoluene/ml as an antioxidant. The solution was vortexed for 1 minute, centrifuged for 2 minutes at 15,000 r.p.m. and the organic phase analyzed by HPLC. HPLC conditions have been reported previously (Qu et al., 2009; Qu et al., 2011). Briefly, we used an isocratic elutent consisting of 1% sodium acetate 3% glacial acetic acid, 5% butanol in methanol at 0.6 ml/minute. The HPLC column was 50×2.1 mm, C-18, 2.6 u, 100 Å (Phenomenex, Torrance, CA). A PDA detector set at 290 nm for ubiquinol and 275 nm for ubiquinone was used. We determined relative ubiquinol and ubiquinone concentrations by their online absorption spectra using extinction coefficients of 14,200 M−1 cm−1 at 275 nm in ethanol for ubiquinone and 4640 M−1 cm–1 at 290 nm in ethanol for ubiquinol (Lester et al., 1959).
Analysis of ATP synthesis in mouse brain homogenates
To produce homogenates of mouse brain, the frontal lobe was homogenized using two strokes of a Potter S homogenizer (Sartorius AG, Goettingen, Germany) at 4°C (20 mg of brain to 1 ml buffer A). The homogenate (80 µl) was added to buffer A (920 µl) and treated as described above for liver samples. Reactions were run in triplicate and data obtained between 5 and 50 minutes after lysis. ATP production showed a linear increase during this time, which was fitted to a line, the slope of which is reported as the relative ATP synthesis rate.
Analysis of ATP synthesis in mouse lens and heart homogenates
Lenses from mice were homogenized (KONTES® DUALL® tissue grinder with glass pestle) in ATP assay buffer (0.15 mM sucrose, 0.5 mM EDTA, 5 mM magnesium chloride, 7.5 mM sodium phosphate, 2 mM HEPES) at 50 µl buffer per lens. We added 1 µl of P-a stock (1 mM) and 1 µl of ADP stock (10 mM) to 100 µl lens homogenate. The mixture was exposed to red light (671 nm at 0.8 W/m2) or kept in dark for 20 minutes. ATP concentrations were determined using a luciferase-based ATP quantification kit according to the manufacture’s instructions (Life Technologies, Grand Island, NY).
Heart tissue (20 mg) was homogenized as above in 1 ml ATP assay buffer. 10 µl of P-a (1 mM) and 10 µl of ADP (10 mM) and 940 µl of ATP assay buffer were added into 40 µl tissue homogenate. The mixture was exposed to red light and ATP was determined as described above using a luciferase based ATP kit.
Analysis of ATP concentrations in duck adipose
We removed visceral fat from a duck (Anas platyrhynchos domestica) less then 30 minutes after death by decapitation and homogenized the fat at 4°C (without buffer) in a loose-fitting Potter-Elvehjem homogenizer. We then added P-a (70 µl of a 3.3 mg/ml stock solution) and ADP (800 µl of a 10 mg/ml stock solution). The homogenate was divided into two groups: one group was kept in the dark, while the other was exposed to red light (671 nm at 0.8 W/m2); both dishes were kept at 37°C. 200-µl aliquots were taken from each dish and ATP was measured using the luciferase assay or by HPLC, as described in the literature (Ally and Park, 1992).
Analysis of the effect of light wavelength
The entire brain of a mouse was homogenized with a Dounce homogenizer (20 mg of brain to 1 ml buffer C: 0.15 mM sucrose, 0.5 mM EDTA, 5 mM MgCl2, 7.5 mM Na2HPO4, 2 mM HEPES) at 4°C. We took a 40-µl aliquot of the homogenate and added it to 940 µl buffer C. We added 10 µl P-a (from a 1 mM stock in DMSO) and placed the sample on ice for 1 hour. We then added 10 µl ADP (from a 10 mM stock). Five 100-µl portions of the suspension were added to each well of a 96-well plate and exposed to light for 40 minutes. Then, 20-µl aliquots of the mixture were lysed with 200-µl lysis buffer for 1 hour on ice, and ATP levels were determined as above using a luciferase-based ATP kit.
Analysis of red fluorescence in tissue extracts
The chlorophyll-rich diet (Harlan Teklad, Indianapolis, IN) contained 15% by weight spirulina [a food supplement produced from cyanobacteria (Ciferri, 1983)], which is equivalent to ∼0.15% by weight chlorophyll-a. The control diet was a purified diet devoid of dietary chlorophylls (Harlan Teklad). The swine chlorophyll-rich diet has been described previously (Mihai et al., 2013).
For fluorescence spectroscopy, five pigs each were given these respective diets ad libitum for 2 weeks. Whole brain or 2–7 grams of abdominal fat was homogenized with a hand-held homogenizer (Omni Micro Homogenizer (μH), Omni International, Kennesaw, GA), HPLC grade acetone (40 ml) was added and the sample was vortexed for 1 minute. Insoluble material was precipitated by centrifugation and the acetone evaporated with a rotary evaporator. The samples were resuspended in 3 ml chloroform and measured directly.
For HPLC and UV spectroscopy, we extracted 2.5 grams of fat, as described above, from rats or swine that had been given a chlorophyll-rich diet, to give a clear oil. We then added 10 ml of absolute ethanol, cooled the sample to −20°C for 30 minutes, pelleted the insoluble material by centrifugation, separated and evaporated the ethanol with a rotary evaporator and re-suspended the sample in 500 µl of absolute ethanol. For plasma, we added 4 ml of plasma to 1 ml of saturated NaCl and 10 ml ethyl acetate, vortexed the sample for 1 minute and separated the layers by centrifugation. We removed the ethyl acetate layer, evaporated the ethyl acetate and re-suspended the resulting film in 300 µl of absolute ethanol. The samples were then used for HPLC and UV spectroscopy. A Waters (Milford, MA) HPLC system with a 600 pump, a 2475 fluorescent detector, a 2998 photodiode array (PDA) detector and a C18, 2.6 u, 100 Å, 150×2.10 mm column (Phenomenex, Torrance, CA) was used for HPLC. Excitation was set to 410 nm and emission set to 675 nm. Absorbance between 275 and 700 was recorded. We used a mobile phase of acetonitrile containing 10% isopropyl alcohol and 0.1% formic acid (solvent A) and water containing 0.1% formic acid (solvent B). Compounds were eluted at a flow rate of 0.3 ml/minute with a 50∶50 mixture of A∶B for 5 minutes, which was changed linearly to 100∶0, A∶B over 15 minutes. At 35 minutes, the flow was increased to 0.5 ml/minute.
In vivo imaging
Animals were imaged with a Maestro™ In-Vivo Imaging System (CRi, Hopkinton, MA), as described by Bouchard et al.; the animals were skinned to reduce interference from skin autofluoresence (Bouchard et al., 2007).
General C. elegans maintenance
Worms were a gift from Dr Cristina Lagido (Department of Molecular and Cell Biology, University of Aberdeen Institute of Medical Sciences, Foresterhill, Aberdeen, UK) (Lagido et al., 2009; Lagido et al., 2001). Nematode husbandry has been described previously (Wood, 1988). Briefly, animals were maintained on nematode growth medium (NGM) agar (Nunc) using E. coli strain OP50 as a food source. To obtain synchronous populations, we expanded a mixed population on egg yolk plates (Krause, 1995). Worm eggs were isolated from the population by treatment with 1% NaOCl/0.5 M NaOH solution (Emmons et al., 1979) and transferred to a liquid culture with E. coli strain OP50, carbenicillin (50 µg/ml) and amphotericin B (0.1 µg/ml; complete medium).
Real-time ATP monitoring in C. elegans
We administered the P-a chlorophyll metabolite by adding it to the culture medium for a minimum of 24 hours. To confirm P-a uptake, we washed away the culture medium containing P-a, suspended the worms in fresh medium and determined the fluorescence spectra in the worms. Treated worms had signature chlorophyll-derived fluorescence, whereas control worms that were not given P-a exhibited no such fluorescence, confirming metabolite uptake.
Worms were grown in liquid culture at a density of 10,000 worms/ml. Twenty-four hours before the experiment, the culture was split into control and treatment groups and varying amounts of a P-a stock solution in DMSO were added to the treated groups. Control worms were given DMSO vehicle. Worms were washed with M9 buffer (IPM Scientific, Eldersburg, MD) to remove food and unabsorbed P-a and resuspended at 3000 worms/ml. 50 µl of worm suspension from each of these groups were plated into a well of a 96-well plate. Each experimental group was plated into a minimum of 12 wells. To assay ATP stores by luminescence, 100 µl of luminescence buffer containing D-luciferin was added to each well, according to the literature (Lagido et al., 2009; Lagido et al., 2001) and luminescence was recorded in a plate reader. The luminescence buffer was a citric phosphate buffer at pH 6.5, 1% DMSO, 0.05% Triton X-100 and D-luciferin (100 µM). After initial ATP measurements, half of the worms from each experimental group were exposed to LED light centered at 660 nm at 1±2 W/m2; the other half was kept in the dark by covering the plate with aluminium foil. ATP (luminescence signal) was recorded periodically. The amount of ATP synthesized was reported as the difference within an experimental group between the luminescence signal of worms kept in the dark and the worms exposed to light. All experimental procedures outside of red light exposure were performed under dim light. The experiment was repeated three times with different populations of worms.
Worms were plated as above, with each experimental group divided into 12 wells of a 96-well plate. Four identical 96-well plates were made, each containing worms treated with varying concentrations of P-a and control worms. At time zero, 100 µl of luminescence buffer was added to a plate and in vivo ATP was assayed as luminescence. The remaining three plates were exposed to light and ATP assays were performed every 15 minutes for 45 minutes by the addition of 100 µl of luminescence buffer and the recording of luminescence.
In vitro ATP monitoring in C. elegans
One-day-old adult worms in liquid culture were incubated with P-a for 24 hours, washed with M9 buffer and re-suspended in M9 buffer at 50,000 worms/ml. The control group was incubated in DMSO vehicle without P-a. 100 µl of each worm suspension was placed into 18 centrifuge tubes. At time zero, six tubes from each group were placed in liquid nitrogen and the remaining tubes exposed to red light. Then, at 15 and 30 minutes, six tubes from each group were placed into liquid nitrogen. To measure ATP, we removed the centrifuge tubes from the liquid nitrogen and placed them in boiling water for 15 minutes to lyse the worms (Artal-Sanz and Tavernarakis, 2009). The resulting solution was cleared by centrifugation for 5 minutes at 15,000 rpm and ATP in the lysate was measured using the luciferase assay according to the manufacturer’s instructions or by HPCL according to established protocols (Ally and Park, 1992).
Analysis of C. elegans oxygen consumption
Oxygen consumption was measured using a Clark-type oxygen electrode (Qubit Systems Inc.), as described (Anderson and Dusenbery, 1977; Zarse et al., 2007). One-day-old adult worms in liquid culture at a density of ∼10,000 worms/ml were incubated with P-a (25 µM) for 24 hours in complete medium. Animals were washed three times with M9 buffer to remove bacteria and excess P-a and resuspended in M9 buffer at 10,000 worms/ml. One-ml aliquots of this suspension were transferred into the respiration chamber and respiration was measured at 25°C for 10 minutes while being exposed to an LED light centered at 660 nm at 1±2 W/m2. The control group was treated in the same way but not incubated with P-a.
Analysis of ROS formation in C. elegans
ROS formation was quantified as described by Schulz et al. (Schulz et al., 2007). Three-day-old worms were synchronized in liquid culture at a density of 500 worms/ml in complete medium, then divided into control and treatments groups. The treatment group was incubated for 24 hours with 12 µM P-a and the control group in DMSO vehicle. Bacterial food and P-a were removed by three repeated washes with M9 and the worms resuspended to 500 worms/ml M9 buffer. 50 µl of the suspension from each group was added to the wells of a 96-well plate with opaque walls and a transparent bottom. A 100 µM 2′,7′-dichlorofluorescin diacetate (Sigma-Aldrich, St. Louis, MO) solution in M9 buffer was prepared from a 100 mM 2′,7′-dichlorofluorescin diacetate stock solution in DMSO. 50 µl of this solution were pipetted into the suspensions, resulting in a final concentration of 50 µM. Additional controls included worms without 2′,7′-dichlorofluorescin diacetate and wells containing 2′,7′-dichlorofluorescin diacetate without animals; these were prepared in parallel. Five replicates were measured for each experimental and control group. Immediately after addition of 2′,7′-dichlorofluorescin diacetate, the fluorescence was measured in a SpectraMax M5 microplate reader (Molecular Devices, LLC, Sunnyvale, CA) at excitation and emission wavelengths of 502 and 523 nm. The plates were then exposed to red LED light and fluorescence was re-measured at 2.5 and 5 hours under conditions equivalent to those used previously.
Life span analysis
Life span measurements were performed according to the method of Gandhi et al. and Mitchell et al. (Gandhi et al., 1980; Mitchell et al., 1979) with some modifications. Eggs were harvested and grown in darkness in a liquid culture at room temperature. To prevent any progeny developing, 5-fluoro-2′-deoxyuridine (FUDR) (Sigma-Aldrich, 120 µM final) was added at 35 hours after egg isolation, during the fourth larval molt. At day 4 of adulthood, the culture was split into control and experimental groups. The experimental group was treated with 12 µM P-a from a stock solution in DMSO. The control group was given the DMSO vehicle alone. The treated and control cultures were then split into two or three. The final density of worms in all reaction flasks was 500 worms/ml; each flask contained 10 ml, therefore a total of 5000 worms. The following day (day 5 of adulthood), worms were exposed to LED light centered at 660 nm at 1±2 W/m2 for 5 hours. Light exposure was repeated every day until the end of the experiment. For counting, aliquots were withdrawn and placed in a 96-well plate to give ∼10 worms per well; the worms were scored dead or alive on the basis of their movement, determined with the aid of a light microscope. A total of 60–100 worms (representing 1–2% of the total population) were withdrawn and counted at each time point for each flask. Counts were made at 2–3-day intervals and deaths were assumed to have occurred at the midpoint of the interval. Any larvae that hatched from eggs produced before the FUDR was added remained small in the presence of FUDR and were not counted. We used the L4 molt as time zero for life span analysis. To obtain the half-life, we plotted the fraction alive at each count verses time and fitted the data to a two-parameter logistic function using the software GraphPad Prism (GraphPad Software, Inc., La Jolla, CA). The two-parameter model is known to fit survival of 95% of the population fairly accurately (Vanfleteren et al., 1998). Because changes in environment, such as temperature, worm density and the amount of food, can influence life span, control measurements were conducted at the same time under identical conditions. The concentration of P-a dropped (∼75%) throughout the life span studies and it was not adjusted (supplementary material Fig. S4F).
Life span measurements in 96-well microtiter plates
Life span was measured as described in the literature (Solis and Petrascheck, 2011), except that P-a was added at day 4 and light treatment commenced at day 5. Scoring (fraction alive) was done once on day 15.
The authors declare no competing interests.
C.X. conducted studies with worms, and ATP measurements in mitochondria and tissue homogenates. J.Z. conducted ATP measurements in mitochondria and tissue homogenates. D.M. conducted metabolite-binding distribution studies. I.W. designed and supervised the study and wrote the manuscript.
This work was supported by the Department of the Navy, Office of Naval Research [grant number N00014-08-1-0150 to I.W.]; the Nanoscale Science and Engineering Initiative of the National Science Foundation [grant numbers CHE-0117752, CHE-0641532 to I.W.]; and the New York State Office of Science, Technology and Academic Research (NYSTAR).
Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.134262/-/DC1
- Received April 30, 2013.
- Accepted October 15, 2013.
- © 2014. Published by The Company of Biologists Ltd
Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.
Though research on migraines has come a long way, the reason why some people are much more prone to them is largely still a mystery. Physicians will often try to find the cause of recurrent migraine attacks by evaluating patients for other underlying medical conditions, food intolerances and sleep problems.
New research suggests doctors may want to consider screening for something even more simple: vitamin deficiencies. Recent work presented June 10 at the 58th Annual Scientific Meeting of the American Headache Society in San Diego finds that certain vitamin supplements could potentially help stop the occurrence of frequent migraines.
In a study on children, teens and young adults, the researchers found migraineurs (people who suffer from frequent migraine headaches) were much more likely to have mildly lower levels of vitamin D, riboflavin (B-2) and coenzyme Q10 (a naturally occurring, vitamin-like enzyme made by the body). All of these vitamins are needed for the mitochondria, the energy production centers of our cells, to function properly. “Deficient function, possibly through vitamin deficiency or over-utilization of vitamins, may put the migraineur at increased risk of energy deficiency,” says Dr. Andrew Hershey, director of the Migraine Center at the Cincinnati Children’s Hospital Medical Center and one of the researchers working on the project.
For the study, researchers at Cincinnati Children’s looked at existing data on 7,691 young patients who were migraine sufferers and their records of blood tests for baseline levels of vitamin D, riboflavin, coenzyme Q10 and folate. Of the study participants, 15 percent were found to have riboflavin levels below the standard reference range. A significant number of patients—30 percent—had coenzyme Q10 levels at the low end of the standard reference range. Significantly lower vitamin D was seen in nearly 70 percent of the patients.
The researchers also found that patients with chronic migraines were more likely to have coenzyme Q10 deficiencies than patients who had episodic migraines. Girls and young women were more likely than boys and young men to have coenzyme Q10 deficiencies at baseline. Boys and young men were more likely to have vitamin D deficiency, but the reasons behind these trends need further investigation. It is important to note that both Q10 and D3 can be created in the body by exposure to the sun.
Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-5′-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight
From here PUBMED
What if conventional wisdom regarding our most fundamental energy requirements has been wrong all along and we can directly harness the energy of the Sun when we consume ‘plant blood’?
Plants are amazing, aren’t they? They have no need to roam about hunting other creatures for food, because they figured out a way to capture the energy of the Sun directly through these little light-harvesting molecules known as chlorophyll; a molecule, incidentally, which bears uncanny resemblance to human blood because it is structurally identical to hemoglobin, other than it has a magnesium atom at its core and not iron as in red blooded animals.
The energy autonomy of plants makes them, of course, relatively peaceful and low maintenance when compared to animal life, the latter of which is always busying itself with acquiring its next meal, sometimes through violent and sometimes through more passive means. In fact, so different are these two classes of creatures that the first, plants, are known as autotrophs, i.e. they produce their own food, and the animals are heterotrophs, i.e. they depend on other creatures for food.
While generally these two zoological classifications are considered non-overlapping, important exceptions have been acknowledged. For instance, photoheterotrophs — a sort of hybrid between the autotroph and heterotroph — can use light for energy, but cannot use carbon dioxide like plants do as their sole carbon source, i.e. they have to ‘eat’ other things. Some classical examples of photoheterotrophs include green and purple non-sulfur bacteria, heliobacteria, and here’s where it gets interesting, a special kind of aphid that borrowed genes from fungi to produce it’s own plant-like carotenoids which it uses to harness light energy to supplement its energy needs!
To learn more about this amazing creature read the study published in 2012 in Scientific Reports titled, “Light- induced electron transfer and ATP synthesis in a carotene synthesizing insect.”
A green carotenoid tinted aphid that is capable of capturing sunlight to produce energy. Interesting right? But we need not look for exotic bacteria or insects for examples of photoheterotrophy. It turns out that animals, including worms, rodents and pigs (one of the closest animals to humans physiologically), have recently been found to be capable of taking up chlorophyll metabolites into their mitochondria, enabling them to use sunlight energy to ‘super-charge’ the rate (up to 35% faster) and quantity (up to 16-fold increases) of ATP produced within their mitochondria. In other words, a good portion of the animal kingdom is capable of ‘feeding off of light,’ and should be reclassified as photoheterotrophic!
The truly groundbreaking discovery referred to above was published last year in the Journal of Cell Science in a study titled, “Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP“, [contact me for the full version: email@example.com] which I reported on recently, and which completely overturns the classical definition of animals and humans as solely heterotrophic.
Animals are Not Just Glucose-Burning Biomachines, But Are Light-Harvesting Hybrids
For at least half a century it has been widely believed among the scientific community that humans are simply glucose-dependent biomachines that can not utilize the virtually limitless source of energy available through sunlight to supplement our energy needs. And yet, wouldn’t it make sense that within the extremely intelligent and infinitely complex design of life, a way to utilize such an obviously abundant energy source as sunlight would have been evolved, even if only for the clear survival advantage it confers and not some ethical imperative (which is a possibility worth considering … vegans/Jainists, are you listening?).
As the philosopher of science Karl Popper stated, a theory can only be called scientific if it is falsifiable. And indeed, the scientific theory that humans are solely heterotrophic has just been overturned in light of empirical evidence demonstrating that mammals can extract energy directly from sunlight.
Deeper Implications of the New Study
First, let’s start by reading the study abstract, as it succinctly summarizes what may be of the most amazing discoveries of our time:
Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy in the form of adenosine-59-triphosphate (ATP) is thought to be limited to chlorophyll-containing chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans [roundworm] leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in mice, rats and swine when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.”
And so, to review, the new study found that animal life (including us, mammals) are capable of borrowing the light-harvesting capabilities of ‘plant blood,’ i.e. chlorophyll and its metabolites, and utilize it to photo-energize mitochondrial ATP production. This not only helps to improve energy output, but the research found several other important things:
- Despite the increased output, the expected increase in Reactive Oxygen Species (ROS) that normally attends increased mitochondrial function was not observed; in fact, a slight decrease was observed. This is a highly significant finding, because simply increasing mitochondrial activity and ATP output, while good from the perspective of energy, may accelerate aging and other oxidative stress (ROS) related adverse cellular and physiological effects. Chlorophyll, therefore, appeared to make animal mitochondria function in a healthier way.
- In support of the above finding, worms administered an optimal range of chlorophyll were found to have significant extended life span. This is in accordance with well-known mechanisms linked to improved mitochondria function (in the absence of increased ROS) that increases cell longevity.
The last point in the abstract above is especially interesting to me. As a fan of coenzyme q10 supplementation for sometime, I have noticed profound differences qualitatively between ubiquinone (the oxidized form) and ubiquinol (the reduced, electron rich form), the latter of which has lead me to experience far greater states of energy and well-being than the former, even at far lower quantities (the molecular weight of a USP isolate does not reveal its bioavailability nor biological activity). The study, however, indicates that one may not need to take supplemental coenzyme Q10, even in its reduced form as ubiquinol, because chlorophyll-mediated sunlight capture and subsequent photo-energization of the electron transport chain will naturally ‘reduce’ (i.e. donate electrons) ubiquinone converting it into ubiquinol, which will result in increased ATP production and efficiency. This may also explain how they observed no increase in ROS (reactive oxygen species) while increasing ATP production: coenzyme q10 in reduced form as ubiquinol is a potent antioxidant, capable of donating an electron to quench/neutralize free radicals. This would be a biological win-win: increased oxidative phosphyloration-mediated energy output without increased oxidative damage.
From here: GreenMedInfo
And of course see more at Nutrition Facts
Hershey says the study adds to an ongoing observation that a significant number of people with migraines have lower levels of these vitamins. However, this trend is not seen in all patients across the board.
It’s been suggested for some time that vitamins play a role in this painful and debilitating chronic condition, but research on the topic is inconsistent. For example, a 2014 analysis in BioMed Research International of seven previously published papers on migraines and vitamin D deficiency suggested there isn’t enough evidence to back the claim that lower levels of the vitamin could make a person more prone to migraines. The researchers of that study found vitamin D deficiency in 13.2 to 14.8 percent of migraine patients. These rates didn’t differ widely from the general population.
Even though evidence is limited, the nutraceutical industry has picked up on the potential for vitamins to alleviate and control migraines. A number of over-the-counter supplement cocktails are currently marketed to migraine sufferers. These typically combine the vitamins identified in this study, as well as magnesium, an organic mineral that when deficient has also been found to increase risk for chronic migraines. One study published in May in International Clinical Psychopharmacology found the odds of acute migraine headaches increased 35.3 times in patients who were identified as magnesium deficient. However, Hershey questions the use of magnesium supplements for treating migraines because he says only about 1 percent is absorbed by the body, and it is also difficult to measure in the blood.
In general, taking these vitamin supplements at recommended doses probably can’t hurt, but much more research is needed to determine whether vitamins alone could help stop migraines. One challenge researchers face is that vitamin supplements are often an intervention used in addition to medications and other experimental therapies. It’s therefore difficult to determine whether improvements in the condition can be explained for reasons other than supplement use
BOCA RATON, FL–(Marketwired – May 12, 2016) – Cubic Pharmaceuticals, a company based in the UK that focuses on developing and distributing high-quality, unique medicines and supplements, announced its Cubicole D3 is more available in the US Market than ever, on Amazon.com and the supplement can help people manage depression.
“It is incredible that research has found Vitamin D to be effective with anti-depressants and to help manage the disorder. It is unbelievably important in this day and age to have more effective treatments for depression when millions of people worldwide are diagnosed with it,” said Saumil Bhatt, CEO of Cubic Pharmaceuticals.
An international study has discovered taking Vitamin D can have a potential impact on mental health and clinical depression according to a recent article on dailymail.co.uk. Vitamin D had been found to increase the effectiveness of antidepressants and Dr. Jerome Sarris, who led a study by ARCADIA Mental Health Research Group at the University of Melbourne, described the results as significant.
Sarris discovered Vitamin D, also known as the sunshine vitamin, has been found to boost mood in combination with anti-depressants. These results were determined after researchers examined 40 clinical trials worldwide, where participants were prescribed with Vitamin D, some other nutraceuticals and placebo pills. Participants who took the Vitamin D supplement experienced less symptoms of depression than those taking the placebo.
Results of the trial is linked to certain receptors in the brain for vitamin D and these receptors are found in the areas of the brain that are linked to the development of depression. For this reason, vitamin D has been linked with depression, according to the Vitamin D Council, and the supplement may increase the amount of monoamines, which can help treat depression.
“People with depression now have a Vitamin D supplement to try in combination with medication to bring results and better treat their condition. I hope with Cubicole D3 more people can treat depression than ever,” Bhatt said.
Cubic Pharmaceuticals Ltd was founded in 2008 and by two pharmacists, Mr. Arun Jangra and Mr. Anwar Ali, who brought in their substantial experience of pharmacy and formulations whilst working with NHS. Since its inception, Cubic Pharmaceuticals Ltd has distributed and traded Ethical, Generics, OTC and Unlicensed Medicinal Products (SPECIALS) sharing knowledge and experiences. For more about the brand, visit: http://www.cubicpharmaceuticals.co.uk.
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
Dr Gitte Bloch Rasmussen, Aarhus University Hospital, Denmark
The news was announced in Rome today by the Danish medical doctor and PhD Gitte Bloch Rasmussen, speaking at ECTS 2016, the 43rd annual congress of the European Calcified Tissue Society (ECTS).
Dr Rasmussen was reporting on trials that had been conducted among 193 women with low levels of vitamin D, who were all planning pregnancy and all attended a single centre in Aarhus, Denmark. The trials had been conducted by Dr Rasmussen with colleagues from Aarhus University Hospital, in Denmark.
Dr Rasmussen said:
Fertile women are often found to have low vitamin D levels, which are associated with low birth weight, reduced fertility and adverse pregnancy outcomes. Our aim was to look at the effects of vitamin D supplements on these areas in women with low levels of vitamin D.
The 193 women were aged 20 – 40, were planning pregnancy and had levels of 25-hydroxyvitamin D (known as 25OHD, the most accurate way to measure vitamin D levels) below 50 nmol/L, which is bordering on insufficiency. Before conceiving, they were allocated to groups, one being given a 70mcg daily supplement of vitamin D3 and one a 35mcg daily dose, with matching groups given placebos. The women continued the trial until 16 weeks after birth and were evaluated for their 25OHD level, birth weight, fertility and any complications.
56% of the women conceived within 12 months, 38% in the placebo group, 29% taking the 70mcg supplement and 33% taking the 35mcg supplement. 44% did not conceive.
Dr Rasmussen continued:
We found a noticeable difference in two of the four areas we evaluated. Whilst the lower daily dose of vitamin D3 did not significantly affect the chances of pregnancy, the higher 70mcg daily supplement significantly reduced the chances of conceiving. On the other hand, supplementation showed to be beneficial on risk of complications during labour, as these were significantly less frequent in the combined vitamin D3 groups (a 23% risk) than in the placebo group (a 52% risk).
However, birth weight did not differ significantly between those treated with vitamin D3 and those receiving placebos; there were also no differences between groups on any safety measures.
Dr Rasmussen concluded:
High doses of vitamin D3 may reduce the likelihood of conceiving, but may also be associated with fewer complications during childbirth, though without improving birth weight.Source:
New research has established that high doses of vitamin D supplements can lead to fewer complications during childbirth but reduce a woman’s chances of getting pregnant in the first place.
Amazon.com: Infectious Burden: The Cause Of Aging And Age-Related Disease eBook: Michael Lustgarten: Kindle StoreAuthor: SupremePundit
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Which grain is the best source for protein, essential amino acids, BCAA and arginine? | Michael LustgartenAuthor: SupremePundit
Listed below are total protein, essential amino acids, branched chain amino acids, and arginine content for quinoa, oats, corn, millet, barley, brown rice and potato. The values provided are for 100 calories, for each respective grain.
Let’s ask some questions:
1. Is there a difference in protein content among these 7 grains?
Yes, there is a difference. Per 100 calories, oats are king, containing more than 2x the amount of protein in barley, the lowest ranking grain on this list. In fact, oats, quinoa and corn each have approximately 2x more total protein than each of the lowest ranking grains, potato, brown rice and barley. Millet is intermediate, at 2.95 grams of protein per 100 calories.
2. Can these grains be considered as “complete protein”?
A “complete protein” is defined as containing all of the 10 essential amino acids (EAA). As shown in the table below, each of the 7 grains contains all of the 10 essential amino acids. Oats contain the greatest amount of essential amino acids (Total EAA), followed by corn and quinoa.
3. Which grain contains the highest amount of branched chain amino acids (leucine, isoleucine and valine)?
The branched chain amino acids (BCAA) leucine, isoleucine and valine are well documented to stimulate muscle protein synthesis (Blomstrand et al. 2006). Oats, corn and millet contain the highest amounts of total BCAA, followed by quinoa, brown rice, potato and barley.
4. Which grain is highest in arginine?
Arginine is the required precursor for the production of nitric oxide (NO), which has been claimed to promote vasodilation in active muscle during exercise, thereby improving strength, power and recovery (Alvares et al. 2011). As shown in the table below, once again, oats contain the highest amount of arginine, followed by quinoa and brown rice.
1) Oats contain the highest amount of total protein, relative to the other grains on this list.
2) All of the 7 grains on this list contain milligram amount of all of the 10 essential amino acids, making each of them a complete protein. Oats contain the highest total amount of essential amino acids, relative to the other grains on this list.
3) Oats also contain the highest amount of branched chain amino acids and arginine, when compared with all the other grains on this list.
Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011 Mar 1;41(3):233-48.
Blomstrand E, Eliasson J, Karlsson HK,Köhnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006 Jan;136(1 Suppl):269S-73S.
Nutritional data provided by http://www.nal.usda.gov/fnic/foodcomp/search/
Listed below are total protein, essential amino acids, branched chain amino acids, and arginine content for quinoa, oats, corn, millet, barley, brown rice and potato. The values provided are for 10…
There are as many as 100 thousand kinds of proteins that constitute the body, and these comprise only 20 kinds of amino acids in various combinations. These 20 kinds of amino acids are essential to the body. In addition to being the materials for proteins, they are used as an energy source for the body as necessary.
Further, each amino acid plays an important and unique role in the body. The list below shows the role of each amino acid.
All of these 3 amino acids are called branched chain amino acid (BCAAs). They perform the important functions of increasing proteins and serving as an energy source during exercise. more info. Alanine It is an important amino acid as an energy source for the liver. more info. Arginine It is an amino acid needed to maintain normal functions of blood vessels and other organs. more info. Glutamine It is an amino acid needed to maintain normal functions of the gastrointestinal tract and muscles. more info. Lysine It is a representative essential amino acid and tends to be insufficient when we are on a bread- or rice-centered diet. more info. Aspartic acid It is contained in asparagus in large amounts. It is a fast-acting energy source. more info. Glutamate It is contained in wheat and soybean in large amounts. It is a fast-acting energy source. more info. Proline It is the main component of “collagen” which constitutes the skin and other tissues. It serves as a fast-acting energy source. more info. Cysteine Cysteine is easy to be deficient in the infants. more info. Threonine It is an essential amino acid which is used to form active sites of enzymes. Methionine It is an essential amino acid which is used to produce various substances needed in the body. Histidine It is an essential amino acid which is used to produce histamine and others. Phenylalanine It is an essential amino acid which is used to produce various useful amines. Tyrosine It is used to produce various useful amines and is sometimes called aromatic amino acid together with phenylalanine and tryptophan. Tryptophan It is an essential amino acid which is used to produce various useful amines. Asparagine It is an amino acid which is located close to the TCA cycle (place of energy generation) together with aspartic acid. Glycine It is used to produce glutathione and porphyrin, a component of hemoglobin. Serine It is used to produce phospholipids and glyceric acid.
For 100 years, since the discovery of glutamate, a kind of amino acid and the source of umami, the Ajinomoto Group has developed our business around the world.
Gelatin is my new favorite superfood! It’s rich in protein, great for your joints, skin, hair, digestive system, immune system, and is accessible and affordable
Gelatin may conjure images in your mind of that slimy, unnaturally green and orange dessert you got in the cafeteria with your school lunches, but dessert made with gelatin is just the tip of the iceberg when it comes to using this potent superfood. Gelatin is a byproduct of meat processing and comes from the bones and connective tissues of animals. It may sound unsavory, but these parts of animals are actually extremely good for you.
There was a time when people consumed nearly all of an animal, while today we simply end up with the processed and packaged meat, or muscle tissue. What we are missing out on are the nutrients found in those discarded parts. When you buy and use pure gelatin in your smoothies, you are adding back in important amino acids that have many benefits for your health.
Gelatin is composed primarily of collagen, the protein that makes up the connective tissues, bones, and skin of animals, like cows and chickens. It includes several amino acids, the building blocks of protein, but does not provide a complete complement of those needed in the human diet. Gelatin is highest in the amino acids glycine and proline.
Gelatin is used in many industries, not just for food. It is used in photography, pharmaceuticals, glues, and cosmetics. In the food industry, gelatin is used for its ability to act as a gelling agent. You will find it in the ingredient list for any gummy candy, marshmallows, but also in margarine, yogurt, cream cheese, and low-fat processed foods. Gelatin is not a vegan food, but there are substitutes if you don’t eat meat. These include agar and carrageen, both of which come from seaweed. Gelatins labeled as kosher are often vegan.
Health Benefits of Gelatin
So why should you add gelatin to your smoothie recipes? There are many reasons. The amino acids that are prevalent in gelatin have great health benefits, and most of us don’t get enough of them in our diets. Here are the top health benefits attributed to gelatin.
Protein: Why consider using unnatural, processed protein powders when you have this natural source available? Gelatin contains between six and twelve grams of protein in every tablespoon. It does not include a complete protein, but it is a significant source of many of the amino acids you need in your diet.
Digestion: Gelatin naturally attracts and binds water to itself, which means that when you add it to your diet, foods that you consume move more easily through your digestive tract.
Detoxification: Glycine, one of the main components of gelatin, is an amino acid that helps the liver function well. You need your liver functioning because it is responsible for eliminating toxins from the bloodstream.
Joint Health: There has been some research that indicates gelatin can help promote healthy joints and bones. Gelatin comes from the joints and bones of animals, so it only makes sense that it would help with ours. The proteins in gelatin may help prevent the degeneration of collagen that occurs naturally with aging. It has even been shown that eating gelatin reduces stiffness and pain in joints afflicted with arthritis.
Skin, Hair, and Nails: Eating gelatin regularly promotes healthy skin, nails, and hair because these tissues are made largely of proteins. Gelatin can make hair and nails stronger and less brittle, and improve the elasticity and appearance of skin. Although there is little evidence, some people claim gelatin also reduces the appearance of cellulite.
Sleep: It’s glycine to the rescue again. This amino acid has been proven to increase the quality of sleep when consumed regularly. Getting more glycine in your diet will also reduce your drowsiness during the day.
Weight Loss: Gelatin may increase the amount of human growth hormone that your body produces. This in turn helps to increase your metabolism so that you burn more calories. Additionally, the high protein content of gelatin means that it keeps you feeling full longer.
Ulcers: Gelatin has even been shown to reduce the size of stomach ulcers. It is believed to act by healing and strengthening the mucous lining of the stomach, which helps to heal ulcers, but also to prevent them from forming in the first place.
Are all gelatins the same? No. Some gelatins have additives. Look for the highest quality gelatin that is 100 percent pure. See my recommended brands below under where to buy.
Do vegan substitutes for gelatin have the same nutrient profile? Unfortunately, no, the seaweed substitutes do not have the same superfood components that gelatin does. Carrageen and agar are largely made up of complex carbohydrates and fiber. They may not have the same health properties as gelatin, but they can be used when you need a gelling agent for a recipe.
Is bone broth the same thing as gelatin? If you do any research into the health benefits of gelatin, you will see bone broth come up again and again. In the past when people ate most of the parts of animals out of necessity, the bones went into the soup pot to make a broth. This broth contains the same proteins as gelatin. You can make bone broth and get the same health benefits as you will with gelatin, but it’s a lot more work.
What does gelatin taste like? Gelatin has no flavor. The gelatin that you see in dessert packets at the grocery store have had flavorings and sugar added. Pure gelatin without those additives is flavorless, which means you can add it to anything.
Gelatin in Smoothies
You truly can add gelatin to any smoothie you make because it has no flavor. Consider replacing your processed protein powder with this pure and natural protein source that will also give you so many other health benefits.
You can experiment with the amount of gelatin that you add to your recipes, but one tablespoon per smoothie serving is a good general rule. If you find that the gelatin clumps up in your smoothie, there are a couple of things you can try. Dissolve your gelatin in a small amount of warm water, or whatever liquid is going into your smoothie, and then add it to the blender. Another option is to use hydrolysate gelatin, which dissolves in cold liquids.
Here’s one of my favorite gelatin containing smoothies. For all of my smoothies featuring gelatin, click here.
Blueberry Gelatin Protein Smoothie
- 1 cup milk (coconut, almond, hemp, or my favorite, raw milk)
- 1/2 avocado, seed removed
- 1 cup frozen blueberries
- 1 tablespoon gelatin
- 1 tablespoon coconut oil
- A dash of cinnamon
- A little honey, maple syrup, or stevia to sweeten
Place all of the ingredients into your high-speed blender and blend for around 30-45 seconds or until nice and smooth. Note, if you don’t have a very powerful blender you might want to blend everything except the coconut oil first, then drizzle it on and blend for another 5-10 seconds to avoid clumping.
I’d love to know if you use gelatin in your smoothies or cooking and what health benefits you have experienced – please divulge in the comments below.
Where to Buy Gelatin
Your local health food or grocery store likely carries gelatin. There are two brands of gelatin I recommend. Bernard Jensen’s 100% Pure Gelatin and Great Lakes Kosher Gelatin. Jensen’s gelatin contains a whopping 15 grams of protein per serving (1 tablespoon).
Sources for this blog post include:
Fish oil, Vitamin D and other nutrients appear to raise the potency of medication
The multibillion-dollar supplement industry spews many dubious claims, but a new study suggests that some nutritional supplements, including omega-3 fatty acids and vitamin D, may boost the effectiveness of antidepressants. If so, the supplements might help relieve symptoms for the millions of people who don’t immediately respond to these drugs.
The meta-analysis—published Tuesday in the American Journal of Psychiatry—reviewed the results of 40 clinical trials that evaluated the effects of taking nutritional supplements in conjunction with several major classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants. It revealed that four supplements in particular upped the potency of the medications, compared with a placebo.
The researchers, based at Harvard University and the University of Melbourne, found the strongest evidence for an omega-3 fish oil called eicosapentaenoic acid, or EPA. In general, people with depression who took an antidepressant drug and an omega-3 sourced from fish oil experienced a significant reduction in their symptoms as assessed by a the Hamilton Depression Rating Scale, a common measure used by most of the studies in the review. The same was true, although to a lesser extent, for S-adenosylmethionine, methylfolate (a form of the B vitamin folic acid) and Vitamin D. A few isolated studies found some benefit from augmenting treatment with creatine, while adding zinc, vitamin C, the amino acid tryptophan and folic acid produced mixed results. The authors deemed all of these supplements relatively safe.
Lead study author Jerome Sarris of the University of Melbourne’s ARCADIA Mental Health Research Group notes that a large percentage of people with depression do not fully respond during one or two trials of an antidepressant. By some estimates, two-thirds don’t respond to the first antidepressant they try and a third fail to get better after several treatment attempts. “The implications are that clinicians and the public can consider [adding] therapeutic doses of nutrients such as omega-3s as a potential low-cost approach to reducing depression in people who are non-responsive to antidepressants,” he says.
Sarris and his colleagues speculate that the supplements may enhance the efficacy of antidepressants in various ways, perhaps directly by altering neurostransmitter activity or indirectly by reducing inflammation, known to contribute to depression. Leading nutritional psychiatry researcher Felice N. Jacka of Deakin University and the University of Melbourne explains that conditions like depression can trigger a cascade of physical concerns that certain supplements, when combined with accepted antidepressant therapies, could help mitigate.
“Serious illnesses such as major depression can result in increased inflammation and oxidative stress, which can in turn result in nutritional deficiencies and a depletion of essential fatty acids,” she notes. “Nutrients form the substrate of the essential biological processes of the body and brain, so ensuring that nutrient levels are adequate in patients suffering from any serious illnesses is important.”
Doctors and scientists often come down hard on nutritional supplementation. There is little to no scientific evidence backing many of the products crowding the shelves at health food stores and pushed by celebrity doctors. In fact, many come in mega-doses associated with serious side effects. And countless manufacturers produce these supplements, many with no standardized processes and varying degrees of quality control.
Indeed, the supplement industry exists largely outside of any oversight by the Food and Drug Administration (FDA). In December last year, the FDA announced the formation of a new Office of Dietary Supplement Programs to help tighten regulation, but for now when it comes to supplements, consumers often don’t know what they are getting.
Sarris acknowledges that supplements can differ greatly in quality and that his results should be approached with caution. “We’re not telling people to rush out and buy buckets of supplements,” he wrote in a press release accompanying the new paper. “Always speak to your medical professional before changing or initiating a treatment.”
But researchers like Sarris are gradually disentangling potential fact from fiction. A number of vitamins and supplements are coming under scientific scrutiny. Vitamin D in particular has been the focus of a host of recent studies and may be beneficial in treating a variety of conditions, from multiple sclerosis to schizophrenia.
For brain health, all—or at least most—roads lead to the sea. Many small trials have reported associations between omega-3 fatty acids—obtained either through diet or supplements—and improved depression symptoms. In practice, omega-3s derived from fish appear to reach significantly higher blood levels than those sourced from plants. And there is a fast accumulating body of data linking a reduced risk for depression to traditional diets—including the Mediterranean, Scandinavian and Japanese diets—that are high in vegetables, whole grains and fish.
How does the evidence sit in light of the new study’s findings? “It is important to advise that a balanced whole-food diet is important for physical as well as mental health, and that supplements should not replace this,” Sarris notes. “However, I believe a good diet in addition to select nutraceutical prescriptions can still be recommended in some cases, such as when people have inadequate responses to antidepressant medication.”
As a next step, Sarris believes that researchers should move beyond specific supplements and study augmenting antidepressant treatment with, say, the Mediterranean diet. Both he and Jacka also feel that more work needs to be done to determine which supplements may benefit patients as individuals, based on their specific nutrient deficiencies, brain conditions and genetic profiles.
“A key imperative for nutritional psychiatry is to develop a clear understanding of what supplements are useful for whom, and under what conditions, and also to understand the baseline factors that might influence nutrient metabolism, such as gut health,” Jacka says. “This sort of knowledge should help us to begin to design targeted and personalized nutritional interventions for psychiatric illnesses.”
A diet heavy on white bread and other high-glycemic index (GI) foods may increase an individual’s risk of lung cancer, according to a new study.
The prohibition of MDMA and hallucinogenic mushrooms restricts “cognitive liberty,” according to some activists.
By the time drug-policy lawyer Charlotte Walsh took to the stage on the final day of the recent Horizons Psychedelic Conference, we had already heard several persuasive talks on the benefits of psychedelic substances. Rick Doblin had spoken about the successful treatment of PTSD with MDMA, Draulio Barros de Araujo described his work combatting depression with ayahuasca, and Stephen Ross discussed his study administering psilocybin to cancer patients.
I had met Ross two years prior, while covering his psychedelic research. The psychiatrist had spent years and a small fortune obtaining the government’s permission to run an extremely limited study. The stakes were high. Without exemptions from the DEA and other agencies, Ross and his NYU team could have faced punishments as severe as life imprisonment. But the risk was worth it: The researchers were able to critically reduce end-of-life anxiety in the vast majority of their patients with targeted therapy aided by a single dose of psilocybin.
These clinical gains run counter to increasingly prohibitive trends exemplified by Holland’s 2008 ban on hallucinogenic mushrooms and the U.K.’s Psychoactive Substances Act of 2016. This recent law automatically renders illegal all substances capable of altering emotions or mental functioning unless specifically exempted.
According to Charlotte Walsh of the anti-prohibitionist Ayahuasca Defense Fund, that kind of blanket drug prohibition is a violation of international human-rights law. Walsh sees parallels between the drug war and the legal battles for racial equality, as well as gay and reproductive rights. She and her colleagues across Europe and North America hope to use the U.S. Bill of Rights and the European Charter on Human Rights to build a cognitive-liberty-based case against drug prohibition.
I spoke with Walsh recently about her current efforts and the prospects for success at home and abroad.
Morin: What would a human-rights-based drug defense look like?
Walsh: Generally, when people are prosecuted for psychedelic use, the defense focuses on technicalities rather than challenging the prohibitive framework itself. On the rare occasions when they do challenge prohibition, they tend to employ a rights-based framework—namely, arguing that their client’s human rights have been infringed by psychedelic drug prohibition. Rights-based defenses have historically been either pleas for therapeutic or religious exemptions from prohibition.
Morin: What is the legal basis for drug prohibition?
Walsh: Within the parameters of the U.K. Misuse of Drugs Act [equivalent to the U.S. Controlled Substances Act] the issue is ostensibly based around the idea of harm. We have an Advisory Council on the Misuse of Drugs, which is a group of scientists in different realms that the government consults when a drug is going to be scheduled or reclassified. The council then carries out a wholesale review of the substance and makes a recommendation for or against prohibition or reclassification. There has been a trend though where the government will ask the Advisory Council to carry out such a review and then just completely ignore their results and do what they want to do. As a stark example, when MDMA was being reevaluated for reclassification, before the results were even in, they issued a public statement saying, effectively, “Don’t worry, whatever they find, we’re not going to change anything.”
An alcohol user can alter their consciousness freely despite the proven risks while a psychedelic user faces heavy punishment.
Morin: What results have they been ignoring?
Walsh: There was an extensive U.K. government study carried out in 2010 by a team under David Nutt that measured various substances in terms of harms to society and the individual. That study showed that alcohol is the overall forerunner in terms of harm, and tobacco comes close after that. A lot of the Class A drugs [equivalent to Schedule I in the US] and psychedelic drugs in particular were at the opposite end of that scale showing very low risk of harm.
Morin: Did the government refute the study or did they ignore it?
Walsh: They basically ignored it. In relation to the alcohol and tobacco findings, obviously nobody has called for their prohibition. An alcohol user can alter their consciousness freely despite the proven risks while a psychedelic user faces heavy punishment. It’s arbitrary discrimination. The government’s response to the Nutt study has been that drug policy isn’t based solely on science, it’s also based on cultural and historical precedent.
Morin: Is that an admission that the harm-based justification for prohibition no longer applies?
Walsh: It’s certainly evidence that it’s applied inconsistently and arbitrarily. From a human-rights-based perspective, everybody’s rights should be protected equally unless there’s a good reason why you’re treating a group differently. I don’t think that saying “culturally and historically this is what we’ve always done” is legitimate. You can’t say that about racial discrimination, for instance.
Morin: So, the current argument is that illegal drugs are bad because they’re illegal?
Walsh: Basically, and it goes beyond that. We have a recently elected Conservative government in the U.K., and they’ve produced something called the Psychoactive Substances Act. It’s a piece of legislation that renders it unlawful to trade in any substance capable of producing a psychoactive effect of any kind regardless of harm or benefit. If you read the text of the Act, it’s extraordinary, most notably its lack of any reference to the concept of harm.
Morin: How do they define “psychoactive” exactly?
Walsh: Any substance that alters your emotional state or mental functioning. It openly states that we [the government] think we have the right to stop you from altering your psychological state. It’s strange that’s something they believe they should have the power to do.
Morin: I assume there are exemptions for alcohol, tobacco, and caffeine.
Walsh: Yes, for culturally accepted substances. This legislation is potentially so broad that prior to its enactment the government felt compelled to write to bishops to reassure them that the incense used in church services would not become illegal, despite its being mildly psychoactive.
Morin: What does that kind of blanket ban indicate to you in terms of legislative intent?
Walsh: The tradition in English law was always to intervene as little as possible. That concept has been dying in more recent years. This reverses that presumption, replacing it with an assumption that you can’t do something unless the government explicitly says you can. This violates classic liberalism, where you have the concept of limitations of power, as most famously espoused by legal theorist John Stuart Mill. How much power can the state legitimately hold over the individual? Mill laid down the principle as prevention of harm to others. So, from that perspective, the kind of paternalism we’re seeing, both in the operation of the Misuse of Drugs Act and the fundamental aims of this new piece of legislation is illegitimate.
Even if you could make a case for that kind of paternalism, how can imprisonment possibly be for our own good?
Morin: Paternalism in terms of protecting people from themselves?
Walsh: Exactly. It’s inherently infantilizing. Even if you could make a case for that kind of paternalism, how can imprisonment possibly be for our own good? In the majority of cases, the primary and often only harm being suffered by the individual is due to the punishment imposed rather than from the substance use itself.
Morin: How do you intend to build a human-rights case against drug prohibition?
Walsh: There are different ways in which you can approach it. Article 8 [in the European Convention on Human Rights] guarantees the right to privacy. In Mexico, there was a Supreme Court ruling that for individuals to grow and use cannabis was a human right connected to the right to privacy. Here in the U.K. recently, there was an all-party parliamentary group looking at drug-policy reform, and one of the things that they said is that drug-possession laws are potentially a breach of our Article 8 right to privacy. That’s the first time I’ve ever seen an official source using that kind of human rights-based argument. I think that is a really promising development.
Morin: The suggestion is that drug use should be a private choice?
Walsh: It should be a private choice as long as it doesn’t harm others. The vast majority of police stops and searches in our streets are for drugs rather than anything else, which is an obvious violation of privacy. Read more broadly, the right to privacy equates with our ability to become who we want to be. Mill, again, was a strong proponent of experiments in living as an important means for self-discovery. The question is, should we be entrusting the government to determine what’s valuable to us? It’s through our own choices, including whether or not to ingest substances, that we engage in a process of self-creation.
Morin: It seems like there are stronger laws in place to prevent a patient from being medicated against their will than there are permitting self-medication. How similar are those two concepts?
Walsh: It’s based on the same argument—the freedom to control your own consciousness and the mechanisms of your thinking. With psychedelics, it’s one of those areas where people who have experienced profound alterations of consciousness will often see merit in these arguments, and people who haven’t are often not very open to them. I think you have to be very careful about how you construct your argument. It’s about liberty. It’s about an abuse of state powers. You want to get people on board who are aren’t necessarily interested in altering their consciousness, but who are interested in curbing what the state can and can’t do.
Morin: Medical arguments have broadly relaxed prohibition of marijuana in this country. Do you see that extending further?
Walsh: I do, but I also think that the medical model is problematic in its own right. I think we need more of a holistic definition of health. Right now, we’re talking about simply the absence of illness—whether it’s physical or mental. We should be talking about allowing individuals to flourish, to develop beyond basic well-being.
Morin: Besides the right to privacy, what other rights do you see influencing the legitimacy of prohibition?
Walsh: Article 9 guarantees religious freedom, so, basically, if you consider the drug you use to be a sacrament, then banning it is a form of religious persecution. In the States, you have a more doctrinal approach to what constitutes a religion. There’s a test. Is there a holy book and a central belief system? There’s a list of things you can work through. In Europe, we don’t have that. We have this loose interpretation of what religious belief is. It can even cover atheism, for example. Indeed, any belief system of significance to you can potentially be covered. The court tends to accept that, but then they say that your ability to manifest that religious belief—for example by drinking ayahuasca—has to be balanced against the public interest in you not doing it. And so, in cases involving ayahuasca, they’ve said that its illegality is proof of its danger, which in and of itself proves that the public interest in your not taking it outweighs your interest in taking it. It’s a circular argument that renders the whole process absolutely meaningless.
Morin: Taking your example, can you talk about why someone would want to use ayahuasca?
Walsh: There have been a lot of studies, and the overall conclusion seem to be that the long-term psychological well-being of people who use it is actually higher than control groups who have never used it. It has thousands of years of cultural history behind it. Then, of course you have the anecdotal evidence of many individuals saying that using ayahuasca has been a very beneficial and transformative experience.
Morin: A lot of people seem to think that the religious argument has the best chance of succeeding here in the U.S.
Walsh: Right. It has already been successful in the U.S. Courts have allowed exemptions in certain cases with ayahuasca, and with the Native American Church and peyote. There have been similar rulings in other countries—Holland and Chile, for example, but nothing like that here in the U.K. Interestingly, in the U.K., judges rejecting human-rights arguments have argued that they are bound by the international system of drug prohibition and therefore can’t make exemptions. In U.S. courts though, that sort of argument has been discarded with barely a second glance. The prosecution has raised the fact that exemptions are against international law and the judiciary has said that it doesn’t trump religious freedom.
Morin: If religious freedom is weaker in the U.K., is there a freedom of speech argument that could be made instead?
Walsh: More broadly under Article 9 is the right to freedom of thought, which is closely linked to freedom of speech, given that our thoughts precede our speech. From that perspective, the idea is that we should be allowed to think what we want—and it’s not just the actual contents of thinking that are important here, but also the processes of thinking. If psychedelics and other drugs can allow you to access different mind states, by preventing access, we’re interfering with true freedom of thought. These substances, as precursors, allow you to think in entirely different ways—which can be beneficial. The idea that psychedelics can actually improve an individual’s life is rarely taken into account, and taking them because they give pleasure is not even considered—as if pleasure were something to be ashamed of. The individual shouldn’t be required to prove that these substances are risk-free, because few things in life are—rather it should be up to the state to prove, with scientific evidence, that the risks justify the damage to our civil liberties. In the absence of that, it is impossible that say that this is truly a free society.
Eating at least one serving of seafood a week could help stave off Alzheimer’s disease, according to a study.
A strong case has been building for the role that omega-3 fatty acids found in fish could play in protecting against Alzheimer’s and other forms of dementia. But questions remained about whether these benefits could be canceled out by the mercury in fish, which at high enough levels can be toxic to the brain. The new study suggests that is not the case.
Researchers delved into the complicated relationship between seafood, fatty acids, mercury and dementia among older adults living in the Chicago area. They surveyed the group about their diet every year starting in 1997, and in a subset of 286 participants who died between 2004 and 2013, they performed brain autopsies to look at the levels of mercury and whether there was neurological damage indicative of dementia.
There was indeed more mercury in the brains of participants who reported eating more seafood, but it did not appear to have any effect on whether there was neurological damage. Instead, participants who reported eating seafood at least once a week were less likely to have hallmarks of Alzheimer’s disease, including amyloid plaques, in their brain.
“The findings were very striking,” said Martha Clare Morris, director of nutrition and nutritional epidemiology at Rush University Medical Center.
“Our hypothesis was that seafood consumption would be associated with less neuropathology, but that if there were higher levels of mercury in the brain, that would work against that. But we didn’t find that at all,” said Morris, who is lead author of the study, which was published Tuesday in the Journal of the American Medical Association.
The catch, however, is that the researchers only observed the benefit among participants who had a strong genetic risk factor for Alzheimer’s. These participants carried a version of the APOE gene called APOE-4, which is associated with higher risk of developing Alzheimer’s.
The researchers ranked the amount of neurological damage they observed on a scale of 1 to 4, from no damage to highest level of damage. Among those who had the APOE-4 gene variant, they saw about half a point less in those who ate at least one serving of seafood a week, compared with less than one serving a week.
It is possible that people who do not harbor APOE-4 could still gain some smaller amount of protection from Alzheimer’s from seafood, but the current study was not big enough to detect it, Morris said.
“One theory is that seafood consumption may be more beneficial in older age because, as we age, we lose DHA in the brain,” a molecule that is important to maintain brain health, Morris said. DHA is one of the main fatty acids that can be obtained from fish. People with APOE-4 are thought to lose even more DHA in the brain, so seafood consumption could be even more beneficial to them, Morris added.
The benefit of fatty acid may not be limited to just Alzheimer’s. The researchers found that participants who reported eating a diet rich in a type of fatty acid called alpha-linolenic acid, which is found in vegetable oils, nuts and soy, had less damage in their brain that is characteristic of vascular dementia. Vascular dementia, which is less common than Alzheimer’s, occurs when blood vessels become blocked and cut off oxygen to the brain.
“The evidence is quite clear that people who consume healthier forms of fish [which are baked or broiled rather than fried] are going to end up with healthier brains,” said James T. Becker, professor of psychiatry and associate director of the Alzheimer’s Disease Research Center at the University of Pittsburgh, who was not involved in the current study.
As for whether mercury increases the risk of dementia, “I personally don’t think there’s evidence for it. I think these heavy metals are going to do other things first,” such as causing nerve pain, itching or burning, Becker said.
This study could not rule on whether people who regularly select seafood that tends to be higher in mercury, such as tuna and swordfish, have problems associated with the higher mercury exposure. The researchers did not drill down to find out all the types of fish participants ate.
Morris pointed out that the types of seafood most commonly consumed by Americans — shrimp, salmon, tilapia — are low in mercury. The one exception is canned tuna, which can be high in mercury.
The current study found the benefit of eating seafood for brain health maxes out at one serving per week. More than that did not bestow participants with any additional protection from the types of brain damage associated with dementia.
This suggests that you might not have to meet the 8 ounces of seafood, about two servings, a week that the U.S. Dietary Guidelines recommends to reap the brain health benefits. “Three ounces could give you that protection,” Morris said.
It is still possible that certain kinds of seafood consumption could have a dark side in terms of brain health. “Our findings can’t be generalized to people who are really high consumers of seafood,” Morris said. In the Midwest population in the study, very few ate seafood every day.
The current study did not address whether participants whose brains had endured less damage also exhibited fewer symptoms of dementia when they were alive. However another study will be coming out soon that looks at the relationship between seafood consumption and cognitive decline in this group of older adults, Morris said.
The advice changes all the time
The advice changes all the time
Are the official dietary guidelines useful to average Americans? I’m not so sure.
Every five years, numerous dietary experts are tasked with putting together a summary of the most up-to-date nutritional science. Their end product is intended to be a series of dietary recommendations that will help public-health agencies, health-care providers, and educational institutions create federal nutrition policy, health programs and disease-prevention initiatives.
This past February, the Dietary Guidelines for Americans advisory panel issued a 571-page report that upended a lot of conventional thinking. After reviewing all the data, they eased restrictions on cholesterol and urged us to eat less sugar and meat. But they also introduced concepts of sustainability and “dietary patterns”—which include how much and how frequently we should eat different foods—into the conversation. The official recommendations were released Jan. 7.
The new recommendations feel odd and a bit touchy-feely compared to the previous, more stern editions that had us go low-fat, avoid eggs, and micromanage the molecules of our meals. Yet regardless of whether the suggestions are ultimately right or wrong, there are two main issues that make them just north of useless.
1. The advice changes all the time.
It seems like there’s a giant Price Is Right wheel, but for nutrition advice. Every five years, we give it a spin, and up comes the dietary guidelines.
For example, all that cholesterol that we were supposed to watch is “no longer a nutrient of concern.” So have an egg with your shrimp scampi and don’t worry as much about counting up the grams of fat in your dinner. Remember the added sugars in the low-fat products we ate before? Eat less of those. But wait, there’s more: you can have coffee again!
It’s no wonder that a 2012 survey by the International Food Information Council found that more than half of Americans said it’s easier to do their taxes than to figure out a healthful diet. And 76% stated that all the constant changes to nutritional guidance make it harder to know what to believe.
As the rubric changed, so did the specific foods that we could or couldn’t eat: eggs, no eggs; nuts, no nuts; cholesterol, no cholesterol; don’t drink wine, now you can.
With this level of change and outright reversal of opinion, there’s never any guarantee that this year’s advice will be next year’s advice. This undermines the impact of the guidelines.
2. There’s too much nutritional noise.
The ink on the Dietary Guidelines for Americans wasn’t dry before the vegan Physicians Committee for Responsible Medicine was suing the government. The committee, which has sued over the guidelines in the past, disagreed with the conclusion that dietary cholesterol is not as bad as we thought, worried that the egg and meat industries unduly influenced the recommendations, and didn’t like that the guidelines neglected to tell people to eat less meat.
Some of the criticism has merit: The cattle industry did not like the government telling people about data indicating that red meat (particularly processed meats) can contribute to heart disease and cancer, so its lobbying group convinced a government agency to keep out language stating that you should eat less meat. Congress used the appropriations process to set limits on what the guidelines could even say.
For ordinary Americans, the reversals of recommendations, the lawsuits and the Congressional conflicts of interest all cast doubt on the validity of the guidelines. The combination of these influences makes the dietary guidelines mostly useless for most Americans.
In the midst of all the cacophony, we need dietary principles that we can rely upon. To do this, we might start by looking at the habits of healthy eating practiced in the Mediterranean. This would involve returning to meals at the family table; eating real food (mostly vegetables); and doing that without over-consuming. That’s a three-step healthy prescription that will remain as true today as it will be when the next dietary guidelines come out five years from now.
Raw sprouts. Uncooked and lightly cooked sprouts have been linked to more than 30 bacterial outbreaks (mostly of salmonella and E. coli) in the US since mid-1990s. As recently as 2014, salmonella from bean sprouts sent 19 people to the hospital. All types of sprouts—including alfalfa, mung bean, clover and radish sprouts—can spread infection, which is caused by bacterial contamination of their seeds. “There have been too many outbreaks to not pay attention to the risk of sprout contamination,” Marler says. “Those are products that I just don’t eat at all.” He did add that he does eat them if they’re cooked.
Meat that isn’t well-done. Marler orders his burgers well-done. “The reason ground products are more problematic and need to be cooked more thoroughly is that any bacteria that’s on the surface of the meat can be ground inside of it,” Marler says. “If it’s not cooked thoroughly to 160°F throughout, it can cause poisoning by E. coli and salmonella and other bacterial illnesses.” As for steaks, needle tenderizing—a common restaurant practice in which the steak is pierced with needles or sliced with knives to break down the muscle fibers and make it more tender—can also transfer bugs from the surface to the interior of the meat. If a restaurant does this (Marler asks), he orders his steak well-done. If the restaurant doesn’t, he’ll opt for medium-well.
Prewashed or precut fruits and vegetables. “I avoid these like the plague,” Marler says. Why? The more a food is handled and processed, the more likely it is to become tainted. “We’ve gotten so used to the convenience of mass-produced food—bagged salad and boxed salads and precut this and precut that,” Marler says. “Convenience is great but sometimes I think it isn’t worth the risk.” He buys unwashed, uncut produce in small amounts and eats it within three to four days to reduce the risk for listeria, a deadly bug that grows at refrigerator temps.
Raw or undercooked eggs. You may remember the salmonella epidemic of the 1980s and early ’90s that was linked mainly to eggs. If you swore off raw eggs back then, you might as well stick with it. The most recent salmonella outbreak from eggs, in 2010, caused roughly 2,000 reported cases of illness. “I think the risk of egg contamination is much lower today than it was 20 years ago for salmonella, but I still eat my eggs well-cooked,” Marler says.
Raw oysters and other raw shellfish. Marler says that raw shellfish—especially oysters—have been causing more foodborne illness lately. He links this to warming waters, which produce more microbial growth. “Oysters are filter feeders, so they pick up everything that’s in the water,” he explains. “If there’s bacteria in the water it’ll get into their system, and if you eat it you could have trouble. I’ve seen a lot more of that over the last five years than I saw in the last 20 years. It’s simply not worth the risk.”
First published at http://bottomlinehealth.com/health-insider/6-things-this-food-safety-expert-wont-eatand-one-surprising-food-he-will/ Copyright © 2016 by Boardroom Inc., 281 Tresser Blvd., Stamford, Connecticut 06901-3229. www.BottomLineHealth.com
2015 – Profile in Obsession: Bill Marler, By Naomi Tomky March 24, 2015
2015 – The New Yorker – A Bug in the System
The New Yorker, Wil S. Hylton, February 2, 2015.
2014 – Q&A: Food Safety Lawyer Bill Marler on What Not to Eat
The National Law Journal, Interview with Jenna Greene, November 3, 2014.
2012 – Bill Marler, Attorney, Blogger, and Food Safety Advocate, Talks Turkey (Or Spinach, Rather)
Miami New Times, Interview with Ily Goyanes, November 2.
2012 – Bill Marler Interview, Part Two: His Most Difficult Cases and Lobbying Congress
Miami New Times, Interview with Ily Goyanes, November 14.
2012 – Profiles in Public Health Law: Interview with William “Bill” Marler CDC Public Health Law News, July.
2012 – Food Safety Lawyer Bill Marler On Sprouts, Raw Milk, and Why “Local” Isn’t Always Safer Blisstree.com, Hanna Brooks Olsen, March 5.
2011 – Listeria outbreak draws Seattle lawyer to battle
Associated Press, Shannon Dininny, October 9.
2011 – Food-Borne Illness Attorney: Top Foods to Avoid
ABC News, Neal Karlinsky, September 29.
2011 – How to Keep Food Free of Salmonella: Lawsuits
The Atlantic, Barry Estabrook, August 31.
2011 – More Stomach-Churning Facts about the E. Coli Outbreak
New York Times, Mark Bittman, June 8.
2011 – Bill Marler: A Personal Injury Attorney and More
The Xemplar, Nicole Black, June 1.
2011 – Good Food Hero: Bill Marler, Food Safety Attorney
Good Food World, Gail Nickel-Kailing, May 23.
2011- Poisoned: The True Story of the Deadly E. coli Outbreak that Changed the Way Americans Eat.
Inspire Books, Jeff Benedict, May 15
2011 – New Book Chronicles Islander Marler’s Work.
Bainbride Island Review, Connie Mears, May 13.
2010 – Food Safety Lawyer Puts His Money Where Your Mouth Is
AOL News, Andrew Schneider, September 29
2009 – Food Safety Lawyer’s Wish: Put Me Out of Business
Seattle Times, Maureen O’Hagan, November 23
2009 – WSU Discourse on Food Safety, Courtesy Seattle Lawyer
Kitsap Sun, Tristan Baurick, August 29
2009 – When Food Sickens, He Heads for Courthouse
Minneapolis Star-Tribune, Matt McKinney, June 24
2009 – Bill Marler, The Food-Safety Litigator
Culinate, Miriam Wolf, April
2009 – Food Fight:Bill Marler’s Beef (PDF)
Washington Law & Politics, David Volk, May
2009 – Candidate for Top FSIS Job talks E. coli Testing, Irradiation, Education
The Meating Place, Ann Bagel Storck, February 6
2009 – Five Minutes with Bill Marler, Well Known Lawyer, Food Safety Activist
CattleNetwork, Chuck Jolley, February 5
2009 – Heath Surveillance the Key to Fresh Produce
The Packer, Tom Karst, February 3
2008 – Seattle Food Contamination Expert in China as Tainted Milk Sickens Thousands of Kids
Seattle Health Examiner, September 23
2008 – E. Coli Lawyer Is Busier Than Ever
Associated Press, February 4
2007 – Legally Speaking: The Food Poisoning Lawyer
The Southeast Texas Record, John G. Browning, November 20
2007 – The Nation’s Leading Food-borne Illness Attorney Tells All
Washington State Magazine, Hannelore Sudermann, August
2007 – Back to Court: Burst of E. coli Cases Returns Jack in the Box Litigator to the Scene
Meat and Poultry News, Steve Bjerklie, June 8
2007 – Food Fight
Portland Oregonian, Alex Pulaski, March
2007 – Mr. Food Illness Esquire
QSR Magazine, Fred Minnick, February
2006 – Seattle Attorney Dominates Food-Borne Illness Litigation
KPLU, October 20
2006 – How a Tiny Law Firm Made Hay Out of Tainted Spinach
The Wall Street Journal, Heather Won Tesoriero and Peter Lattman, September 27
2005 – Bill Marler – Education Holds Key in Tainted Food Fight
King County Bar Association Bar Bulletin, Ross Anderson, November
2001 – THE INSIDE STORY: How 11 Schoolkids Got $4.75 Million in E. coli Lawsuit
MeatingPlace.com, Bryan Salvage, March 7
2001 – Hammer Time: Preparation Pays When Disputes Escalate to Lawsuits
Meat & Poultry Magazine, David Hendee
2001 – For Seattle Attorney, A Bacterium Brings Riches—and Enemies
The Wall Street Journal, Rachel Zimmerman
2001 – The Bug That Ate The Burger
Los Angeles Times, Emily Green, June
1999 – Courting Publicity, Attorney Makes Safe Food His Business
Seattle Post, Maggie Leung, September 7
A 2010 article published in Oncology Reports states pancreatic cancer is among the most aggressive forms of human cancer, characterized by a very high mortality rate. It represents the fourth leading cause of cancer death in United States, killing 32,000 people annually. With a 5-year survival rate of only 3 percent and a median survival rate of less than six months, pancreatic cancer carries one of the poorest prognoses. The diagnosis of pancreatic cancer is one of the worst things a doctor ever has to tell a patient. The only FDA-approved therapies for it, Gemcitabine and Erlotinib, produce objective responses in less than 10 percent of patients, while causing severe side-effects in the majority. There is a desperate need for new options.
Clinical research to test new treatments is split into phases. Phase I trials are just to make sure the treatment is safe, to see how much you can give before it becomes toxic. Curcumin, the natural yellow pigment in the spice turmeric has passed a number of those. In fact, there was so little toxicity, the dosing was limited only by the number of pills patients were willing to swallow.
Phase II trials are conducted to see if the drug actually has an effect. Curcumin did, in 2 of the 21 patients that were evaluated. One patient had a 73 percent tumor reduction, but the effect was short-lived. One lesion remained small, but a curcumin-resistant tumor clone emerged. The other patient, who had a stable disease for over 18 months, showed slow improvement over a year. In fact, the only time that patient’s cancer markers bumped up was during a brief three-week stint where the curcumin was stopped.
So curcumin does seem to help some patients with pancreatic cancer, and most importantly, there appears to be little downside. No curcumin-related toxic effects were observed in up to doses of eight grams per day. What happens after eight grams? We don’t know because no one was willing to take that many pills. The patients were willing to go on one of the nastiest chemotherapy regimens on the planet, but didn’t want to be inconvenienced with swallowing a lot of capsules.
The only surefire way to beat pancreatic cancer is to prevent it in the first place. In 2010 I profiled a study conducted by the National Institutes of Health, the largest such study in history, which found that dietary fat of animal origin was associated with increased pancreatic cancer risk.
Which animal fat is the worst? The second largest study has since chimed in to help answer that question. Researchers found that poultry was the worst, with 72 percent increased risk of pancreatic cancer for every 50 grams of daily poultry consumption. Fifty grams is just about a quarter of a chicken breast. The reason white meat came out worse than red may be because of the cooked meat carcinogens in chicken, the heterocyclic amines that build up in grilled and baked chicken. These mutagenic chemicals have been associated with doubling pancreatic cancer risk.
Meat has been associated with significantly increased risk, whereas fake meat is associated with significantly less risk. Those who eat plant-based meats like veggie burgers or veggie dogs three or more times a week had less than half the risk of fatal pancreatic cancer. Legumes and dried fruit appear to be similarly protective.
My grandfather died of pancreatic cancer. By the time the first symptom arose, a dull ache in his gut, it was too late. That’s why we need to work on preventing it.
Carcinogens in grilled and baked chicken may increase the risk of pancreatic cancer, while curcumin may help even in advanced stages of the disease.
Imagine being charged with a DUI when it’s been hours since you’ve had a drink, only to later discover that your body brews its own alcohol.
That’s what happened to an upstate New York woman when she blew a blood alcohol level more than four times the legal limit. Just before Christmas in Hamburg, New York, a judge dismissed the charges after being presented with evidence the woman suffers from “auto-brewery syndrome.”
“I had never heard of auto-brewery syndrome before this case,” attorney Joseph Marusak told CNN on the condition his client’s identity remain anonymous. “But I knew something was amiss when the hospital police took the woman to wanted to release her immediately because she wasn’t exhibiting any symptoms.”
“That prompts me to get on the Internet and see if there is any sort of explanation for a weird reading,” adds Marusak. “Up pops auto-brewery syndrome and away we go.”
“I’m in touch with about 30 people who believe they have this same syndrome, about 10 of them are diagnosed with it,” said Panola College Dean of Nursing Barbara Cordell, who has studied the syndrome for years. “They can function at alcohol levels such as 0.30 and 0.40 when the average person would be comatose or dying. Part of the mystery of this syndrome is how they can have these extremely high levels and still be walking around and talking.”
Extremely rare condition
Also known as gut-fermentation syndrome, this rare medical condition can occur when abnormal amounts of gastrointestinal yeast convert common food carbohydrates into ethanol. The process is believed to take place in the small bowel, and is vastly different from the normal gut fermentation in the large bowel that gives our bodies energy.
First described in 1912 as “germ carbohydrate fermentation,” it was studied in the 1930s and ’40s as a contributing factor to vitamin deficiencies and irritable bowel syndrome. Cases involving the yeast Candida albicans and Candida krusei have popped up in Japan, and in 2013 Cordell documented the case of a 61-year-old man who had frequent bouts of unexplained drunkenness for years before being diagnosed with an intestinal overabundance of Saccharomyces cerevisiae, or brewer’s yeast, the same yeast used to make beer.
Flat tire a blessing
It was a beautiful fall afternoon in 2014 when Marusak’s client met her husband at a restaurant for food and drinks. She consumed “four drinks between noon and 6 p.m.” says Marusak, “less than one drink an hour. We hired a local pharmacologist who said that a woman of her size and weight having four drinks in that period of time should be between 0.01 and 0.05 blood alcohol levels.” That would be beneath the legally impaired level of 0.08 BAC in New York state.
And here’s the “crazy thing,” says Marusak. “Her husband drives to meet friends and she is driving home. She gets a flat close to home but doesn’t want to change the tire so keeps on driving. Another driver sees her struggling with the car and calls it in as an accident. So if she hadn’t had that flat tire, she’d not know to this day that she has this condition.”
Because she blew a blood alcohol level of nearly 0.40, police procedure is to take the accused to a hospital, as that level is considered extremely life-threatening.
Instead of allowing his wife to be released as the hospital recommended based on her lack of drunken symptoms, the husband asked for tests to be run. Sure enough, Marusak says, the results showed a blood alcohol level of 0.30, hours and hours after her last drink. That prompted Marusak to do his own sleuthing.
“I hired two physician assistants and a person trained in Breathalyzers to watch her and take blood alcohol levels over a 12-hour period and had it run at the same lab used by the prosecution,” said Marusak. “Without any drinks, her blood level was double the legal limit at 9:15 a.m., triple the limit at 6 p.m. and more than four times the legal limit at 8:30 p.m., which correlates with the same time of day that the police pulled her over.”
Even more strange, says Marusak, is the fact that the woman exhibited no signs of the levels until she reached a blood alcohol level of between 0.30 and 0.40.
“That’s when she started to feel a bit wobbly on her feet.” Marusak explains that by pointing to the world of alcoholism, where the bodies of “functioning alcoholics” adapt to the high levels of booze in their blood.
Even though the Hamburg judge dismissed the case against his client, Marusak says it’s not over yet.
“I’ve heard the DA’s office says they plan to appeal. I’ll know more by the middle of January.”
Assistant Erie County District Attorney Christopher Belling confirmed a review of the judge’s decision is underway but declined to comment further.
In the meantime, Marusak’s client is treating her condition with anti-fungal medications and a yeast-free diet with absolutely no sugar, no alcohol and very low carbs. While that works for some, Cordell says, others relapse or find little relief
For decades, scientists believed that excess body fat was mere storage for unused calories. However, research conducted over the past 20 years suggests added fat is more than a little extra cushion—fat cells are actually “toxic factories,” each one producing inflammatory cytokines (chemical messengers of inflammation) throughout the body and causing potentially serious damage to your health. It is this understanding that has led experts to more closely examine the effects of being overweight, even when an individual is considered physically fit.
In 1998, the National Institutes of Health (NIH) published Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults. These guidelines noted being overweight but in good physical health would reduce the risk of premature death— in other words, being physically fit mattered more than body fat percentage.
But in 2015, the International Journal of Epidemiology released the results of a study that suggested the “fat but fit” theory wasn’t true, based on the health data of more than 1.3 million Swedish men whom researchers followed for 30 years. Those study authors found that the beneficial effects of exercise declined as obesity rates increased. Compared to physically fit obese men, normal-weight men who were not physically fit had a lower risk of dying.
These results are backed by a prior study published in January 2015 that identified a link between increased levels of fat in the body— regardless of physical fitness— and high levels of inflammation. Inflammation is the root cause of all disease, especially chronic conditions, such as heart disease, diabetes, cancer and Alzheimer’s disease. Another study published in the journal Clinical Cancer Research in 2015 observed a correlation between increased levels of white fat tissue and poorer prognosis in early-stage breast cancer. White fat, known as white adipose tissue, is fat stored for energy, but it also plays a role in raising inflammation levels when found in excess throughout the body.
Abdominal obesity, which is fat centralized in the belly, is a sign of high levels of visceral fat in the body. Visceral fat is the type of fat that accumulates in arteries and around organs, and has been credited with increased inflammation and disease risk. Emerging research has found that while this still holds true, fat may be further differentiated. A December 2014 study found that fat deposits may exist on the surface of the myocardium (muscular wall of the heart) and be contained completely beneath the membrane that encloses the heart— in contact with major coronary arteries and their branches. This fat, known as epicardial adipose tissue (EAT), is highly correlated with obesity, and thought to play a role in the development and vulnerability of plaque in the coronary arteries.
Facebook users recruit friends for diet, supplement programs — but is it legit?
7 reasons why you’re working out and still not losing weight
If being fit doesn’t protect against the dangers of excess weight gain, what can?
While fitness is still an important component of optimal health, it is not a standalone marker.
If you are struggling with losing weight, you will reap significant benefits by increasing lean body mass with exercise.
Here are 3 other tactics that can help you lose weight and lower your disease risk:
1. Assess body fat rather than BMI
One of the primary challenges facing the nation today is the standard of measurement for obesity. At present, obesity is defined by body mass index (BMI), which is essentially a height-to-weight ratio. For example, a man who is 5 feet 10 inches tall weighs 220 pounds and has 12 percent body fat would be considered obese, according to the BMI scale. However, anyone with 12 percent body fat is not overweight or obese. This person is likely a bodybuilder with very high levels of lean muscle. His body fat percentage is a better indicator of his health risk. BMI drastically underscores fat levels in the aging population, particularly postmenopausal women who have lost substantial muscle mass that has been replaced with fat and yet their weight remains steady.
A bioelectrial impedance assessment (BIA) is a more comprehensive look at body composition, assessing lean body mass, body fat, and body water percentages, as well as showing where primary fat stores exist. These assessments are generally available through a physician’s office. Monitoring your body fat rather than BMI will help you better assess your overall health and weight management goals.
2. Add a probiotic to your supplement regimen
Research continues to identify the gut flora as a contributing factor to multiple aspects of health, including weight management and inflammation levels. Unfortunately, the typical American diet often leads to imbalances in the microbiota of the gut favoring the development of intestinal inflammation and increased risk of disease. A daily probiotic (not a dairy-based, sugar-laden probiotic) can help promote healthy bacteria in the gut. According to one study, the Lactobacillus plantarum strain offers the greatest potential for suppressing chronic inflammation in the gut. In November 2015, one study uncovered evidence that the landscape of the bacteria in your gut may be the greatest factor in determining which foods will optimally improve an individual’s weight and general health.
3. Consume a clean, nutrient-rich, whole-foods diet
While certain research may say that the Mediterranean diet is good for some people and that the Paleo diet is good for others, one fact remains: Whole foods are best. Strive to consume a wide variety of fresh vegetables and low-sugar fruits organically or locally sourced. Enjoy a mix of lean proteins from animal sources along with plant-based proteins that are high in fiber, like quinoa. Keep sugar, artificial sweeteners and ingredients, and processed foods out of your diet. These foods contribute to toxins in the body and negatively impact healthy gut microbiota.
Achieving optimal health is always a work in progress. Set small goals every month, week, and day that will drive progress. You don’t have to be perfect, but you should try to make everyday choices, a choice that will maximize your wellbeing— mind, body, and spirit.
Dr. Jennifer Landa is Chief Medical Officer of BodyLogicMD, the nation’s largest franchise of physicians specializing in bioidentical hormone therapy. Dr. Jen spent 10 years as a traditional OB-GYN, and then became board-certified in regenerative medicine, with an emphasis on bio-identical hormones, preventative medicine and nutrition. She is the author of “The Sex Drive Solution for Women.” Learn more about her programs at www.jenlandamd.com.
For decades, scientists believed that excess body fat was mere storage for unused calories.
Desmond just sent me an e-mail with the below summary of an interview that he conducted with Dr. Gerd Lindner (who works with Dr. Roland Lauster) and his PhD candidate student (now doctor?) Beren Ataç at the recent WCHRS2014 in South Korea. At the end of this post, I have embedded the video of Dr. Ataç’s presentation that was also filmed by Desmond.
FYI — Dr. Ataç’s Phd thesis was titled: “Development of a vascularized human hair follicle equivalent” and her mentors for that project included Dr. Gerd Lindner and Dr. Roland Lauster.
Here’s my recount of the discussion I had with Dr Linder & Dr Atac about their work.
Firstly, it is with great excitement to mention that their work into regeneration of a hair follicle did not stop in 2010 after their ground breaking paper was published but rather continued at a remarkable pace with significant breakthroughs being made and some patents filed. Their presentation at the congress gave a great insight into how far along they actually are. It is also important to mention that their lab is subdivided into several teams, each working on regenerating a particular organ of the body such as the liver, kidney and of course the hair follicle.
Their aim is to have at least 10 organ models that are of human origin in order to provide a much better prediction of how a drug would perform in a clinical trial compared to animal studies. A FDA study showed that more than 92% of substances tested in animals show false negative results, and have to be excluded from use in/on humans because of toxic effects. They gave a few examples of where investigational drugs showed to be safe in animal studies but proved to be fatal in human subjects. Tegenero trial being an example.
The hair follicle team (Dr Lindner, Lauster & Atac) have FOUR goals:
1) To create a microchip system where many organs thrive.
2) To create a human hair follicle model that allows rapid screening of compounds that may have an impact on hair regeneration or removal! This may be performed on a single follicle or on a follicle embedded in an engineered full thickness skin equivalent
3) To engineer neopapillae (ECM coated dermal papilla cell spheroids) that will be transplantable into human subjects for patients suffering from Androgenetic Alopecia.
4) and ultimately, to have personalised chips of all genetic backgrounds to give a full picture of pharmacokinetics & pharmacodynamics of an investigational drug.
As for what they have achieved so far:
1) In 2010: Their original paper was published which we are well aware of.
2) In 2011: They bioengineered “human micro-hair follicles” in vitro. These micro-follicles displayed key characteristics of human vellus-like hair follicles. Mesenchymal, ectodermal and neuro-ectodermal originated primary cells from dissected human hair follicles were isolated and expanded. Dermal papilla fibroblasts were kept under low adherent culture conditions (along the same line as the EVAL scaffolds of the Taiwanese that we came across) resulting in the formation of dermal papilla-like aggregates. They then forced keratinocytes and melanocytes to attach to these dermal papilla spheres to allow further follicular development. The result was a self-organizing micro-organoid made up of separate segments enclosed by extracellular matrix membranes, sheath formations and a hair shaft–like fiber. Central ECM proteins and defined mesenchymal and epithelial markers were expressed. Furthermore, inner root sheath formation was found to be present and the melanocyte markers “p-Mel17”, “c-kit” and “TRP-1” were expressed in the supra-papillary region of the microfollicle. These results showed that the de novo formation of human microfollicles in vitro is possible and contains all the basic hair follicle like characteristics.
At this point they realised that after the addition of keratinocytes and melanocytes, the self-organizing micro-organoids followed a stringent pattern of follicular-like formation by generating polarized segments, sheath formations and the production of a hair shaft-like fiber. But the bio-engineered hairs were vellus-like and didn’t turn terminal. This is most probably due to lack of nutrient and oxygen supply during cell culture but may also be caused by an altered gene expression, a problem that Dr Jahoda’s team faced a few years later with their 3D hanging drop spheroid cultures.
Since then, they transferred their culturing method to a perfused bioreactor system and finally came to the conclusion that the best way to improve the microfollicle development is by also co-culturing endothelial cells with the hair follicle which turn into micro-blood vessels and are normally feeding the hair follicles the necessary oxygen, hormones and nutrients. In fact, our hair follicles are very well vascularised, and one can see where they are coming from.
3) So in 2013, they went at it again. They again used an ultra-low adherent attachment conditions. The low-adherent surface which is polycarbonate-based mimics mesenchymal condensation during embryonic development. Under these conditions, DP cells self-aggregate and are then coated with keratinocytes, melanocytes and endothelial cells. After 48 hours the newly formed micro-follicles are placed in a multi-organ chip platform to grow. They also used a new 3D matrix environment to enhance gene expression. These micro-follicles were cultured for 14 days, which showed further improvements in hair follicle-like expressions as you’ll see in the presentation.
So, I guess although they haven’t managed to completely replicate a fully functional (terminal) hair follicle, these follicles look very promising indeed. Some may even call it the endgame (of chess), where there are very few pieces left to play. Exciting times indeed and what a wonderful team of individuals working on such a revolutionary project. The Lauster team as we know them is made up of some great minds: Dr Gerd Lindner and Beren Atac to name a few. I wish them all the very best and I’m sure they’ll have very exciting news to share with the world in a few years.
Early markers of heart disease are worse with depressive symptoms, but that association was lessened or eliminated with regular physical activity, an observational study showed.
Higher Beck Depression Inventory-II scores correlated with more inflammation as indicated by C-reactive protein levels (P<0.001), more oxidative stress assessed by lower antioxidant glutathione (P<0.001), and poorer vascular function measured by both the augmentation index and subendocardial viability ratio (P=0.008 and P=0.001).
Those associations persisted through adjustment for a number of variables, including weight, age, and some cardiovascular risk factors, Arshed A. Quyyumi, MD, of Emory Clinical Cardiovascular Research Institute in Atlanta, and colleagues reported in a research letter in the Jan. 19 issue of the Journal of the American College of Cardiology.
But getting the recommended level of physical activity interacted significantly with depressive symptom scores for inflammation and cardiac function.
“Thus, vascular stiffening and systemic inflammation that accompany worsening depressive symptoms were more pronounced in sedentary subjects, and these relationships were attenuated in subjects engaged in regular moderate to vigorous physical activity,” the researchers wrote.
“Our findings highlight potential mechanisms by which depressive disorders are linked to cardiovascular disease risk, and support the routine assessment of depressive symptoms to improve cardiovascular disease risk stratification,” they concluded. Physical exercise appears to prevent the adverse cardiovascular consequences of depression, but these findings need to be confirmed in a randomized trial.”
Their study included 965 individuals (median age 49) free of heart disease, cerebrovascular, or peripheral arterial disease at baseline who hadn’t previously been diagnosed with any affective, psychotic, or anxiety disorder.
Activity trims inflammation and cardiac function associations
Fecal transplants are not as disgusting as one might imagine they’d be — they actually involve taking pills filled with freeze-dried fecal matter. Taking these pills can help change the communty of organisms living inside the gut, known as a microbiome, and subsequently help fight infections. Research has also shown giving fecal transplants from obese patients to slim patients could help them gain weight. But is the opposite true?
Dr. Elaine Yu, an assistant professor and clinical researcher at Massachusetts General Hospital, hopes so. In a clinical trial, she’s giving 20 obese patients the pills, filled with fecal matter from healthy-weight individuals in order to see how their microbiomes change. “We have no idea what the result will be,” Yu told Ars Technica. But if all goes as planned, the fecal transplants will change not only the patients weights, but also their lean and fat body mass as well as insulin sensitivity — a major contributor to obesity.ADVERTISING
Over the course of 12 weeks, half of the patients will receive a dose of the freeze-dried poop, with the others receiving a placebo pill. The researchers will monitor their progress over the next year, or beyond, depending on how successful their trial is. And the patients will not be on any restrictive diet; they’re expected to continue their current exercise and dietary habits. Fecal samples will also be collected to study the microbiomes of each patient.
Though fecal transplants have been used to alter gut microbiomes before, The New York Times reports the real challenge behind the process was creating suitable capsules for the fecal matter. This is where nonprofit company OpenBiome stepped in and created a capsule that can dissolve in the small intestine, while remaining solid in room temperature. This is important because feces typically dissolves in capsules.
The microbiome consists of trillions of microorganisms and can weigh over 4 pounds. Up to two-thirds of a person’s microbiota is unique to their own bodies, meaning an obese person’s microbiome has a completely different composition than a lean person’s. The microbiome is mostly found in the intestines, where it helps the immune system fight off infections, helps the digestive system handle the food we eat, and produces vitamins B and K. As we grow up, so does our microbiome — babies, who are sterile within the uterus, immediately begin developing their own microbiomes from the air they breathe and the food they eat once they’re birthed.
Right now, Yu and her team hope to find another way to combat obesity. If their trial proves successful, Yu told Ars Technica that the team would be able to do all of the detail-oriented work in order to determine which microbial communities are affected — this would in turn provide the information for more targeted treatments in the gut.